U.S. patent application number 10/586209 was filed with the patent office on 2008-03-20 for controlled release cgrp delivery composition for cardiovascular and renal indications.
Invention is credited to George L. Southard, Jeffrey L. Southard.
Application Number | 20080069865 10/586209 |
Document ID | / |
Family ID | 34794460 |
Filed Date | 2008-03-20 |
United States Patent
Application |
20080069865 |
Kind Code |
A1 |
Southard; Jeffrey L. ; et
al. |
March 20, 2008 |
Controlled Release Cgrp Delivery Composition for Cardiovascular and
Renal Indications
Abstract
The present invention provides methods of treating heart failure
and improving renal function, and/or preventing the advancement of
heart failure into advanced stages, and methods of counteracting
ischemia due to a myocardial infarction by providing improved
methods of administering a therapeutically effective amount CGRP as
a controlled release formulation. The therapies can be administered
on an outpatient or inpatient basis and can further be used as
maintenance therapies.
Inventors: |
Southard; Jeffrey L.;
(Lenexa, KS) ; Southard; George L.; (Sanibel,
FL) |
Correspondence
Address: |
MORRISON & FOERSTER LLP
755 PAGE MILL RD
PALO ALTO
CA
94304-1018
US
|
Family ID: |
34794460 |
Appl. No.: |
10/586209 |
Filed: |
January 13, 2005 |
PCT Filed: |
January 13, 2005 |
PCT NO: |
PCT/US05/01225 |
371 Date: |
November 8, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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60560745 |
Jan 13, 2004 |
|
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Current U.S.
Class: |
424/450 ;
424/494; 424/78.31; 514/12.2; 514/13.5; 514/13.7; 514/15.1;
514/15.4; 514/16.3; 514/16.4; 514/17.4; 514/20.6 |
Current CPC
Class: |
A61P 9/04 20180101; A61K
47/61 20170801; A61P 9/10 20180101; A61P 13/12 20180101; A61K 47/60
20170801; A61K 38/225 20130101; A61K 9/0024 20130101; A61K 9/7007
20130101; A61K 9/1647 20130101 |
Class at
Publication: |
424/450 ;
424/494; 424/78.31; 514/12 |
International
Class: |
A61K 38/23 20060101
A61K038/23; A61K 31/765 20060101 A61K031/765; A61K 9/127 20060101
A61K009/127; A61K 9/50 20060101 A61K009/50; A61P 9/10 20060101
A61P009/10 |
Claims
1. A method of treating heart failure and/or renal failure in a
patient, comprising delivering to said patient CGRP in an amount
effective to provide symptomatic relief, prevent exacerbation of
symptoms, and/or prevent and/or delay progression of the disease
state of heart failure in said patient, wherein said CGRP is
delivered to said patient as a controlled release composition.
2. The method of claim 1, wherein said controlled release
composition comprises a flowable thermoplastic polymer composition
comprising a biocompatible polymer, a biocompatible solvent and
CGRP and said composition is delivered to a bodily tissue or fluid
in said patient, wherein the amounts of the polymer and the solvent
are effective to form a biodegradable polymer matrix containing
CGRP in situ when said composition contacts said bodily fluid
tissue or fluid.
3. The method of claim 1, wherein said CGRP is in the form of a
conjugate comprising CGRP coupled to a polymer.
4. The method of claim 3, wherein said polymer is a poly(alkylene
glycol) or a polysaccharide.
5. The method of claim 2, wherein the composition further comprises
a controlled release additive.
6. The method of claim 2, wherein said CGRP is released from said
polymer matrix at a rate that will maintain circulating plasma
levels of CGRP between 11.+-.5 pg/ml and 186.+-.127 pg/ml over a
period of 7 to 180 days.
7. The method of claim 6, wherein said composition comprises
between about 0.56 and 290 mg CGRP and between about 0.01 and 5.8
mL of said composition is administered to said patient
8. The method of claim 6, wherein said composition comprises about
0.56 and 290 mg CGRP and between about 0.004 and 1.93 mL of said
composition is administered to said patient.
9. The method of claim 2, wherein said biocompatible polymer is
selected from the group consisting of polylactides, polyglycolides,
polyanhydrides, polyorthoesters, polycaprolactones polyamides,
polyurethanes, polyesteramides, polydioxanones, polyacetals,
polyketals, polycarbonates, polyorthocarbonates, polyphosphazenes,
polyhydroxybutyrates, polyhydroxyvalerates, polyalkylene oxalates,
polyacrylates, polyalkylene succinates, poly(malic acid),
poly(amino acids) and copolymers, terpolymers, cellulose diacetate,
ethylene vinyl alcohol, and copolymers and combinations thereof
10. The method of claim 2, wherein the polymer matrix releases CGRP
by diffusion, erosion, or a combination of diffusion or erosion as
the polymer matrix biodegrades in said patient.
11. The method of claim 2, wherein said CGRP is delivered via a
puncture needle or catheter.
12. The method of claim 2, further comprising administering one or
more drugs selected from the group consisting of anti-proliferative
agents, anti-clotting agents, vasodilators, diuretics,
beta-blockers, calcium ion channel blockers, blood thinners,
cardiotonics, ACE inhibitors, anti-inflammatories, and
antioxidants.
13. The method of claim 12, wherein said drug is added to said
polymer composition prior to administration such that said solid
polymer matrix further contains said drug.
14. The method of claim 12, wherein said drug is administered as a
separate formulation before, simultaneously, or subsequently to
administration of said polymer composition.
15. The method of claim 1, wherein said treatment is provided as a
prophylaxis to prevent or delay further progression of said heart
failure and/or said renal failure.
16. The method of claim 1, wherein the length of said treatment is
sufficient to relieve or attenuate one or more symptoms of heart
failure.
17. The method of claim 1, wherein said treatment is sufficient to
improve renal blood flow, glomerular filtration rates, and/or
.serum levels of urea and creatinine in said patient.
18. The method of claim 1, wherein said treatment is sufficient to
improve the quality of life of said patient.
19. The method of claim 1, wherein said patient is a pediatric
patient.
20. The method of claim 1, wherein said controlled release
composition comprises biodegradable microspheres incorporating
CGRP.
21. The method of claim 20, wherein said microspheres comprise
poly(lactic-co-glycolic acid), poly(lactic acid),
poly(caprolactone), polycarbonates, polyamides, polyanhydrides,
polyamino acids, polyortho esters, polyacetals, polycyanoacrylates
degradable polyurethanes, polyacrylates, ethylene-vinyl acetate
copolymers, acyl substituted cellulose acetates, and derivatives
and copolymers thereof.
22. The method of claim 20, wherein said CGRP is in the form of a
conjugate comprising CGRP coupled to a polymer.
23. The method of claim 20, wherein said microspheres are embedded
in a gel matrix.
24. The method of claim 1, wherein said controlled release
composition comprises CGRP encapsulated in a liposome.
25. The method of claim 23, wherein said CGRP is in the form of a
conjugate comprising CGRP coupled to a polymer.
26. The method of claim 23, wherein said polymer is a poly(alkylene
glycol) or a polysaccharide.
27. The method of claim 1, wherein said controlled release
composition comprises CGRP conjugated to a polymer.
28. The method of claim 1, wherein said controlled release
composition is in film form.
29. The method of claim 28, wherein said film comprises polylactic
acid, polyglycolic acid and mixtures and copolymers thereof.
30. A method of treating heart failure and/or renal failure in a
patient, comprising administering a flowable composition comprising
a biocompatible polymer, a biocompatible solvent and CGRP to a
bodily tissue or fluid in said patient, wherein the amounts of the
polymer and the solvent are effective to form said polymer matrix
comprising CGRP in situ when the formulation contacts said bodily
fluid tissue or fluid wherein polymer matrix comprises between
about 5% and 15% CGRP by weight and said CGRP is released from said
polymer matrix at a rate between about 0,0008 and 0.016
.mu.g/min/kg body weight over a period of 7 to 180 days.
31. A method of treating heart failure and/or renal failure in a
patient, comprising: (a) administering CGRP to said patient by a
method selected from parenteral, oral, sublingual, intranasal,
intracoronary, intra-arterial, intravenous, transmucosal, or
intradermal delivery for a time and at a dose effective to provide
symptomatic relief, prevent exacerbation of symptoms, and/or
prevent and/or delay progression of the disease state of heart
failure in said patient; and (b) delivering CGRP to said patient as
a controlled release formulation in an amount effective to provide
symptomatic relief, prevent exacerbation of symptoms, and/or
prevent and/or delay progression of the disease state of heart
failure in said patient.
32. The method of claim 31, wherein said controlled release
formulation comprises a flowable thermoplastic polymer composition
comprising a biocompatible polymer, a biocompatible solvent and
CGRP and said composition is delivered to a bodily tissue or fluid
in said patient, wherein the amounts of the polymer and the solvent
are effective to form a biodegradable polymer matrix containing
CGRP in situ when said composition contacts said bodily fluid
tissue or fluid.
33. The method of claim 31, wherein said controlled release
formulation comprises biodegradable microspheres incorporating
CGRP.
34. The method of claim 31, wherein said controlled release
formulation comprises wherein said controlled release composition
comprises g CGRP encapsulated in a liposome.
35. The method of claim 31, wherein said controlled release
formulation comprises CGRP coupled to a polymer.
36. The method of claim 31, wherein said controlled release
formulation is in film form.
37. A method of preventing or reducing the risk of occurrence of
myocardial infarction, comprising delivering to a human at risk of
having a myocardial infarction a controlled release formulation of
CGRP comprising an amount of CGRP effective to prevent or reduce
the risk or occurrence of myocardial infarction.
38. The method of claim 37, wherein said controlled release
formulation comprises a flowable formulation comprising a
biocompatible polymer, a biocompatible solvent and CGRP wherein
said formulation is delivered to a bodily tissue or fluid in said
patient and a solid polymer matrix containing said CGRP is formed
in situ in said tissue or fluid.
39. The method of claim 37, wherein said controlled release
formulation comprises biodegradable microspheres incorporating
CGRP.
40. The method of claim 37, wherein said controlled release
formulation comprises wherein said controlled release composition
comprises g CGRP encapsulated in a liposome.
41. The method of claim 37, wherein said controlled release
formulation comprises CGRP coupled to a polymer.
42. The method of claim 37, wherein said controlled release
formulation is in film form.
43. A kit comprising a first container comprising a controlled
release formulation of CGRP, said formulation comprising an amount
of CGRP effective to treat or prevent heart failure and/or renal
failure.
44. The kit of claim 43, further comprising one or more drugs
selected from the group consisting of anti-proliferative agents,
anti-clotting agents, vasodilators, diuretics, beta-blockers,
calcium ion channel blockers, blood thinners, cardiotonics, ACE
inhibitors, anti-inflammatories, and antioxidants.
45. The kit of claim 29, further comprising a second container
comprising one or more drugs selected from the group consisting of
anti-proliferative agents, anti-clotting agents, vasodilators,
diuretics, beta-blockers, calcium ion channel blockers, blood
thinners, cardiotonics, ACE inhibitors, anti-inflammatories, and
antioxidants.
46. The kit of claim 29, further comprising a puncture needle or
catheter.
47. A method of counteracting ischemia due to myocardial infarction
in a patient, comprising delivering to said patient an amount of
CGRP effective to provide cardioprotection, reduction in infarction
size, reduction in reperfusion injury, symptomatic relief, and/or
prevent exacerbation of symptoms, wherein said CGRP is delivered to
said patient as a controlled release composition.
Description
[0001] This application claims the benefit of U.S. Provisional
Application Ser. No. 60/560,745, filed Jan. 13, 2004, the
disclosure of which is incorporated herein by reference in its
entirety.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention provides methods for treating heart
failure improving renal function preventing or delaying the
advancement of heart failure into advanced stages, and
counteracting ischemia due to a myocardial infarction by providing
improved methods of administering a therapeutically effective
amount CGRP as a controlled release formulation.
[0004] 2. Description of the Prior Art
[0005] Heart failure is a complex clinical syndrome that can result
from any structural or functional cardiac disorder that impairs the
ability of the ventricle to fill with or eject blood, and the heart
works less efficiently than it should. Heart failure is
characterized by specific symptoms (e.g., dyspnea and fatigue)
which may limit exercise tolerance and signs. (e.g., fluid
retention) which may lead to pulmonary congestion and peripheral
edema. Both abnormalities can impair the functional capacity and
quality of life of affected individuals, but they may not
necessarily dominate the clinical picture at the same time. Because
not all patients have volume overload at the time of initial or
subsequent evaluation, the term "heart failure" is preferred over
the older term "congestive heart failure."
[0006] The clinical syndrome of heart failure may result from
disorders of the pericardium, myocardium, endocardium, or great
vessel. For example, common causes of heart failure include:
narrowing of the arteries supplying blood to the heart muscle
(coronary heart disease); prior heart attack (myocardial
infarction) resulting in scar tissue large enough to interfere with
normal function of the heart; high blood pressure; heart valve
disease due to past rheumatic fever or an abnormality present at
birth; primary disease of the heart muscle itself (cardiomyopathy);
defects in the heart present at birth (congenital heart disease)
and infection of the heart valves and/or muscle itself
(endocarditis and/or myocarditis or pericarditis). The majority of
patients with heart failure have symptoms due to an impairment of
left ventricular function. Each of these disease processes can lead
to heart failure by reducing the strength and efficiency of the
heart muscle contraction, by limiting the ability of the heart's
pumping chambers to fill with blood due to mechanical problems or
impaired diastolic relaxation, or by filling the chambers with too
much blood.
[0007] Renal blood flow is also an important factor in the
development of the clinical syndrome of heart failure. It is a
determinant of some important neurohormonal responses and of salt
and water retention. Renal blood flow is reduced in patients with
HF, and many patients with HF will also eventually develop renal
failure.
[0008] There are four stages of heart failure recognized by the
American College of Cardiology Guidelines for the Evaluation and
Management of Chronic Heart Failure in the Adult. Stage A refers to
patients who are at high risk for developing heart failure but have
no identified structural or functional abnormalities of the heart
and have never shown signs or symptoms of heart failure. If needed,
Stage A patients are prescribed ACE inhibitors to lower blood
pressure and reduce the heart's work load. Stage B refers to
patients who have developed structural heart disease strongly
associated with the development of heart failure but have never
shown signs or symptoms of heart failure. Stage B patients are
typically prescribed ACE inhibitors and beta-blockers that decrease
myocardial oxygen demand and thereby ischemia, and reduce heart
rate and cardiac work. Stage C refers to current or prior symptoms
of heart failure associated with underlying structural disease.
Management of HF at Stage C can involve a triple or quadruple drug
therapy that includes ACE inhibitors, beta-blockers, diuretics, and
Digitalis. Stage D refers to patients with advanced structural
heart disease and marked symptoms of heart failure at rest despite
maximal medical therapy, requiring specialized intervention. Since
HF is a terminal condition, mid and end-stage BF (Stages C and D,
respectively) treatment focuses on alleviating symptoms and
increasing the patient's quality of life such that they can
continue to live a relatively active lifestyle. Successful
management of the progression of heart failure and effective
treatments to relieve heart failure symptoms are determined by
monitoring increases in the heart's ejection fraction, decreases in
dyspnea, and changes in the frequency and/or severity of heart
failure symptoms. However, while current end-stage drug therapies
such as Dobutamine or Milrinone increase the patient's quality of
life, they also have been shown to increase mortality.
[0009] It is estimated that about four million people in the United
States suffer from various degrees of heart failure. Although heart
failure is a chronic condition, the disease often requires acute
hospital care. Patients are commonly admitted for acute pulmonary.
congestion accompanied by serious or severe shortness of breath.
Acute care for HF accounts for the use of more hospital days than
any other cardiac diagnosis, and consumes in excess of seven and
one-half billion dollars in the United States annually.
[0010] Current research into the treatment of chronic heart failure
is focused on providing cardioprotection, myocardial tissue salvage
by minimizing or reducing infarction size, and preventing
reperfusion injury. Many current drug therapies for treating heart
failure address specific clinical aspects associated with
myocardial infarction, such as anti-platelet/fibrinolytic,
anti-inflammatory, and antioxidant activities. Such drugs include
ACE inhibitors to prevent blood vessel constriction and to increase
blood flow to the body, diuretics to remove excess fluid, beta
blockers to reduce heart work load, calcium channel blockers to
increase the blood flow through the heart and prevent vessel
constriction, blood thinners to prevent blood clots, and
cardiotonics to strengthen the heart's ability to pump blood. Only
a few companies to date are developing new drugs that address
tissue salvage, however the effectiveness of these drugs remains to
be established in the clinic. As with all drugs, these agents must
be taken in doses sufficient to ensure their effectiveness.
Problematically, however, over-treatment can lead to hypotension,
renal impairment, hyponatremia, hypokalemia, worsening heart
failure, impaired mental functioning, and other adverse conditions.
Surgical treatments include angioplasty, coronary arty by-pass
grafts, valve replacement, pacemakers, internal defibrillators,
left ventricular assist devices, and heart transplants.
[0011] Heart failure is the number one diagnosis for hospital
admissions in patients over the age of 65. More than $38.1 billion
has been spent annually since 1991 on inpatient and outpatient
costs and greater than $500 million on drugs to treat HF. The
disorder is the underlying reason for 12 to 15 million office
visits each year and 1.7 to 2.6, million hospital admissions each
year. Because of the hospitalization costs required to treat a
heart failure patient, the current trend is to get HF patients into
outpatient care as soon as possible, often within the 48 hours of
hospital admission. Specialized outpatient clinics are now
available for heart failure patients. The patients typically attend
the clinic between one and four times per week to receive
intravenous infusions of a prescribed heart failure therapy until
hemodynamic symptoms improve.
[0012] Calcitonin gene-related peptide ("CGRP") is a 37-amino acid
neuropeptide which is the most potent naturally occurring
vasodilator peptide in the human body. CGRP is distributed
throughout the central and peripheral nervous systems, and is found
in areas that ate known to be involved in cardiovascular function
(Wimalawansa, S., Critical Reviews in Neurobiology, 11:167-239
(1997)). Peripherally, CGRP is found in the heart, particularly in
association with the sinoatrial and atrioventricular nodes. In
addition, CGRP is found in nerve fibers that form a dense
periadventitial network throughout the peripheral vascular system,
including the cerebral, coronary, and renal arteries. CGRP has
prominent cardiovascular effects, including vasodilation and
positive chronotropic and inotropic effects, which may play an
important role in normal cardiovascular function (Wimalawansa, S.,
Endocrine Reviews. 17:208:217 (1996)).
[0013] When administered, CGRP has pronounced cardiovascular
benefits, including vasodilation, ischemic cardioprotection,
reduction in infarction size due to heart attack, inhibition of
platelet aggregation and smooth muscle cell proliferation which can
potentially reduce the incidence of restenosis, increased renal
function, and overall increased efficiency of cardiovascular
functions. As a result of providing cardioprotection, minimizing
reperfusion injury, and reducing infarction size, CGRP also
promotes myocardial tissue salvage. CGRP also plays a role in
regulating inotropy, chronotropy, microvascular permeability,
vascular tone, and angiogenesis. CGRP also has significant
advantages over conventional drug treatments. First, CGRP does not
produce the potentially dangerous side effects, toxicity and
tolerance associated with conventional cardiovascular drugs such as
Nitroglycerin, Dobutamine and Natrecor. In fact, CGRP has been
reported to down-regulate immune response via inhibition of
cytokine release and has been safely administered to
immuno-suppressed subjects without-the induction of sensitivity.
Second, because CGRP has multiple hemodynamic benefits, it can
potentially reduce or eliminate the need for drug cocktails to
maintain specific hemodynamic functions. Third, the biochemical
activity of CORP is mediated through specific receptor binding
sites concentrated in the heart, kidneys, and genitalia, and is
known, to act on two specific CGRP receptor subtypes located on the
surface of the endothelial and smooth muscle cells, respectively.
Accordingly, CGRP exhibits virtually no side effects or tolerance
when administered systemically.
[0014] Studies have demonstrated that acute administration of CGRP
can result in increased cardiac performance and reduced systemic
resistance in a number of clinical scenarios. For example, Anand,
et al. (J. Am. Coll. Cardiol., 17:208-217 (1991)) reported that
short-term IV infusions (10 or 20 minutes) of CGRP at rates of 0.8,
3.2, or 16 ng/kg/min (i.e., 56, 224, or 1120 ng/min based on a 70
kg subject) produced beneficial hemodynamic effects such as
decreased systemic vascular resistance and increase in cardiac
output, with no tachycardia observed. The study concluded that at
lower doses CGRP behaves as a pure arteriolar vasodilator, where as
at the higher dose CGRP acts a mixed vasodilator. Stephenson, et
al. (Int. J. Cardiol., 37:407-414 (1992)) reported administration
of CGRP at a rate of 600 ng/min by either a 48-hour continuous
IV-infusion or 2-8 hour infusions for two consecutive days. In the
continuous infusion therapy, infusion was discontinued after 28
hours in 3 out of the 6 patients due to nausea, diarrhea, and/or
severe facial flushing. On the other hand, the pulsed therapy was
well tolerated and was observed to improve hemodynamic functions
such as left ventricular function. However, unfavorable side
effects of tachycardia and neurohumoral response were also observed
with the pulsed therapy. Sekhar, et al. (Am. J. Cardiol. 67:732-736
(1991) reported administration of CGRP at a rate of 8 ng/kg/min
(i.e., 560 ng/min based on a 70 kg subject) by IV infusion for 8
hours. This therapy was observed to have beneficial hemodynamic
effects such as decreased pulmonary and systemic arterial pressure,
decreased vascular resistance and increased cardiac output. It was
also observed that renal blood flow and glomerular filtration were
increased during treatment. However, the hemodynamic effects were
lost within 30 minutes of stopping CGRP infusion.
[0015] Chronic HF is a progressive disease. Therefore, therapies
that initially seek to reduce disease progression while increasing
the patient's quality of life and relieving symptoms that
exacerbate the condition are desirable. It would be far more cost
effective and much better for the patient's health if chronic heart
failure could be managed and controlled by the routine or
controlled release administration of appropriate drug therapy
rather than by hospital treatment upon the manifestation of acute
symptoms.
SUMMARY OF THE INVENTION
[0016] The present invention provides a method for the treatment or
prevention of heart failure ("HF") by administering one or more
doses of a CGRP formulation in a manner that will treat the
conditions underlying HF while minimizing or attenuating
deleterious effects commonly associated with CGRP such as nausea,
diarrhea, severe facial flushing and intermittent tachycardia. More
specifically, this invention provides improved CGRP dosing regimes
for patients suffering from or at risk for HF, and a method of
treating-HF or delaying the progression of HF into more advanced
stages by providing lower dose and longer term administration of
CGRP.
[0017] Accordingly, one aspect of this invention provides a method
of treating HF in a patient comprising administering CGRP to the
patient such that circulating plasma levels of CGRP are sufficient
to maintain hemodynamic stability, thereby preventing or delaying
exacerbation HF symptoms. In prior clinical studies using Stage C
and D HF patients, effective circulating plasma levels of CGRP were
administered by intravenous infusions ranging between 157.+-.26
pg/mL to 186.+-.127 pg/mL (Anand; et al., 1991 and Shekhar, et al.,
1991, supra). However, these doses could only be administered
intravenously for about 12-24 hours before unwanted side effects
set in and the IV administration had to be discontinued. In
contrast, the methods of the present invention administer CGRP by
controlled release systems or compositions that maintain
circulating plasma levels of CGRP between about 11.+-.5 pg/mL and
186.+-.127 pg/mL for a length of time that is within the
capabilities of the particular controlled release delivery system
or composition.
[0018] In one embodiment, the controlled release composition
comprises a biodegradable polymer matrix containing CGRP, wherein
CGRP is released from the polymer matrix in situ by diffusion or
dissolution from within the polymer matrix and/or by the
degradation of the polymeric matrix. The controlled release
formulation can also be in film form. In another embodiment, the
controlled release formulation comprises solid microparticles
formed from the combination of biodegradable, synthetic polymers
such as poly(lactic acid) (PLA), poly(glycolic acid) (PGA), and
copolymers thereof with CGRP loadings that yield a sustained
release over a period of time when administered orally,
transmucosally, topically or by injection. In further embodiments,
the controlled release formulations comprise CGRP encapsulated in a
liposome or CGRP conjugated to a polymer.
[0019] The above-described methods and controlled release
compositions can further be used for maintenance therapies,
preferably using lower doses or dosing rates of CGRP, after the
initial therapy is completed.
[0020] This invention further provides prophylactic methods of
preventing HF in a patient at risk of HF or slowing the progression
or symptoms of HF in a patient suffering from HF. For example,
another aspect of this invention provides a method of preventing or
reducing the risk of occurrence of myocardial infarction in a
patient, comprising administering to a human at risk of having a
myocardial infarction a controlled release CGRP formulation in an
amount effective to prevent or reduce the risk of myocardial
infarction.
[0021] In all of the above-described methods, the amount of CGRP
delivered to the patient depends on the symptoms, stage of HF,
degree of severity and/or other medications (e.g., diuretics) being
administered to the patient.
[0022] This invention further provides a method of augmenting
current HF therapies comprising administering CGRP according to the
dosing regimes of this invention together with one or more addition
drugs for HF, wherein CORP and the additional drug(s) can be
administered together, separately and simultaneously, or separately
in any order.
[0023] This invention further provides a method of counteracting
ischemia due to myocardial infarction in a patient, comprising
delivering to said patient an amount of CORP effective to provide
cardioprotection, reduction in infarction size, reduction in
reperfusion injury, symptomatic relief, and/or prevent exacerbation
of symptoms, wherein said CGRP is delivered to said patient as a
controlled release composition.
[0024] Another aspect of this invention comprises a method of
improving renal blood flow and glomerular filtration in a patient
suffering from diminished renal function, comprising administering
CGRP to a patient in need thereof in a manner effective to improve
renal blood flow and/or glomerular filtration.
[0025] Administering CGRP according to the methods of this
invention provides a safer and more effective treatment of acute
cardiac ischemia and heart failure compared to current treatments
for HF. Given the advantages in cardioprotection, myocardial tissue
salvage, cardiac hemodynamic improvement, and renal function
provided by CGRP, the methods of this invention have the potential
to be powerful frontline weapons in the arsenal of emergency room
doctors who are the first to treat patients suffering from
myocardial infarction (MI) upon entry into the health care system,
and/or an interventional cardiologist who is working to
re-establishing blood flow to an ischemic heart using angioplasty
or stenting procedures, and/or a cardiologist who is treating mid-
to end-stage heart failure patients to provide increased quality of
life to terminal patients.
[0026] Additional advantages and novel features of this invention
shall be set forth in part in the description that follows, and in
part will become apparent to those skilled in the art upon
examination of the following specification or may be learned by the
practice of the invention. The advantages of the invention may be
realized and attained by means of the instrumentalities,
combinations, compositions, and methods particularly pointed out in
the appended claims.
DETAILED DESCRIPTION OF THE INVENTION
[0027] One aspect of this invention provides improved methods for
administering CGRP to a patient having HF in a manner effective to
treat or prevent HF. The "patient" can be any living organism,
including a warm-blooded mammal such as a human. The treatment
according to any of the methods of this invention can be
administered on an inpatient such as a hospital or emergency room,
or in an outpatient setting such as a hospice or home health care
setting or administration by emergency care personnel to a patient
having a myocardial infarction. This invention further provides
methods of improving hemodynamic functions in a patient with HF by
providing improved methods of administering CGRP to the patient in
either an inpatient or outpatient setting.
[0028] "Treating HF" as used herein refers to treating any one or
more of the conditions underlying HF, including, without
limitation, decreased cardiac contractility, abnormal diastolic
compliance, reduced stroke volume, pulmonary congestion, decreased
cardiac output, and other diminished hemodynamic functions, while
minimizing or attenuating deleterious effects that may be
associated with the long-term administration of CGRP such as
nausea, diarrhea, severe facial flushing and intermittent
tachycardia. "Treating HF" also includes relieving or attenuating
symptoms associated with HF.
[0029] This invention also provides a method of improving the
quality of life in a patient with HF. "Quality of life" refers to
one or more of a person's ability to walk, climb stairs, do
errands, work around the house, participate in recreational
activities, and/or not requiring frequent rest intermittently
during activities, and/or the absence of sleeping problems or
shortness of breath.
[0030] For purposes of this invention, a "patient having HF" refers
to a person having Stage B, Stage C, or Stage D heart failure as
classified in the American College of Cardiology Guidelines for the
Evaluation and Management of Chronic Heart Failure in the Adult.
While the American College of Cardiology Guidelines excluded HF in
children, for purposes of this invention the methods are to be
considered applicable to any patient, regardless of age.
[0031] More specifically, this invention provides improved methods
for providing effective amounts of CGRP for treating or preventing
HF and/or for improving renal function in a patient. In the
treatment of HF according to this invention, compositions
comprising CGRP alone or in combination with other drugs or
therapies will be formulated, dosed, and administered in a fashion
consistent with good medical practice. It is to be understood that
the actual dose will depend on the particular factors of each case.
Generally, the dosage required to provide an effective amount of
CGRP or a pharmaceutically acceptable salt thereof is within the
ranges disclosed herein and can be adjusted by one of ordinary
skill in the art. The dosage will vary depending on the clinical
condition of the individual patient (especially the side effects of
treatment with CGRP alone or in combination with other
therapeutics), the age, health, physical condition, sex, diet and
medical condition of the patient, the severity (i.e., stage) of
heart failure, the route of administration, the site of delivery of
CGRP, the type of drug delivery system that is used, whether CGRP
is administered as part of a drug combination, the scheduling of
administration, and other factors known to practitioners. Thus,
while individual needs may vary, determination of optimal ranges
for effective amounts of CGRP (alone or in combination with other
drugs) within the ranged disclosed herein is within the expertise
of those skilled in the art. Accordingly, "effective amounts" of
each component for purposes herein, are determined by such
considerations and are amounts that improve one or more hemodynamic
functions and/or ameliorate on or more deleterious conditions in HF
patients and/or improve the quality of life in HF patients and/or
improve renal function.
[0032] The term "hemodynamic functions" includes, but is not
limited to, heart rate, right atrial pressure, pulmonary artery
pressure, pulmonary artery wedge pressure, systemic arterial
pressure, cardiac output (i.e., cardiac index), stroke volume
index, pulmonary vascular resistance, and systemic vascular
resistance.
[0033] The term "improved hemodynamic functions" includes, but is
not limited to, increased cardiac output, decreased pulmonary
artery wedge pressure, decreased pulmonary vascular resistance, and
decreased systemic vascular resistance, increased cardiac
contractility, normal diastolic compliance, increased stroke volume
and reduced pulmonary congestion.
[0034] The term "afterload" refers to the resistance that the heart
has to overcome during every beat to send blood into the aorta.
This resistive force includes vasoactivity and blood viscosity.
[0035] The term "cardiac index" (CI) refers to amount of blood
pumped by the heart per minute per meter squared of body surface
area.
[0036] The term "cardiac output" (CO) refers to the volume of blood
pumped by the heart in one minute. Increased cardiac output can
indicate a high circulating volume. Decreased cardiac output
indicates a decrease in circulating volume or a decrease in the
strength of ventricular contraction.
[0037] The term "central venous pressure" (CVP) refers to readings
that are used to approximate the Right Ventricular End Diastolic
Pressure (RVEDP). The RVEDP assesses right ventricular function and
general fluid status. Low CVP values typically reflect hypovolemia
or decreased venous return, and high CVP values reflect
overhydration, increased venous return or right-sided cardiac
failure.
[0038] The term "change in heart rate" refers to a condition that
indicates tachycardia or increased workload.
[0039] The term "dyspnea" means shortness of breath. Dyspnea is a
primary clinical endpoint to address efficacy in heart failure
treatments.
[0040] The term "left ventricular stroke index" (LVSI) refers to
the difference in contractile position of the left ventricle from
the resting position to the point of maximum contraction.
[0041] The term "mean arterial pressure" (MAP) refers to changes in
the relationship between cardiac output (CO) and systemic vascular
resistance (SVR) and reflects the arterial pressure in the vessels
perfusing the organs. A low MAP indicates decreased blood flow
through the organs, and a high MAP indicates an increased cardiac
workload.
[0042] The term "neurohormone release" refers to a response by the
kidneys to increase renal blood flow by releasing the
vasoconstricting neurohormones norepinephrine, epinephrine, and
rennin. These hormones act to constrict peripheral vasculature
adversely affecting the PVR.
[0043] The term "preload" refers to the combination of pulmonary
blood filling the atria and the stretching of myocardial fibers.
Preload is regulated by the variability in intravascular volume. A
reduction in volume decreases preload, whereas an increase in
volume increases preload, mean arterial pressure (MP) and stroke
index (SI). Preload occurs during diastole.
[0044] The term "pulmonary artery pressure" (PA pressure) refers to
blood pressure in the pulmonary artery. Increased pulmonary artery
pressure may indicate a left-to-right cardiac shunt, pulmonary
artery hypertension, COPD, emphysema, pulmonary embolus, pulmonary
edema, or left ventricular failure.
[0045] The term "pulmonary capillary wedge pressure" (PCWP or PAWP)
refers to a pressure are used to approximate LVEDP (left
ventricular end diastolic pressure). High PCWP may indicate left
ventricle failure, mitral valve pathology, cardiac insufficiency,
and/or cardiac compression post hemorrhage. PCWP is a primary
clinical endpoint to address efficacy in heart failure
treatments.
[0046] The term "pulmonary vascular resistance" (PVR) refers to the
measurement of resistance or the impediment of the pulmonary
vascular bed to blood flow. An increased PVR is caused by pulmonary
vascular disease, pulmonary embolism, pulmonary vasculitis, or
hypoxia. A decreased PVR is caused by medications such as calcium
channel blockers, aminophylline or isoproterenol, or by the
delivery of O.sub.2.
[0047] The term "renal blood flow" (RBF) refers to the measurement
of blood flow into the kidneys. Twenty percent of cardiac output
passes through the kidneys, which compromise less than 1% of body
weight. Increased renal blood flow is proportional to increased
renal function and urine output.
[0048] The term "renal glomerular filtration" (RBF) refers to the
first step in urine formation as protein-free ultrafiltrate plasma
crosses the walls of the glomerular capillaries. increased renal
blood flow increases flow of plasma across the glomeruli,
increasing urine output.
[0049] The term "right ventricular pressure" (RV Pressure) refers
to a direct measurement that indicates right ventricular function
and general fluid status. High RV pressure may indicate pulmonary
hypertension, right ventricle failure, or congestive heart
failure.
[0050] The terms "stroke index" or "stroke volume index" (SI or
SVI) are used interchangeably and refer to the amount of blood
ejected from the heart in one cardiac cycle, relative to Body
Surface Area (BSA). SVI is measured in milliliters per meter
squared per beat. An increased SVI can be indicative of early
septic shock, hyperthermia or hypervolemia, or can be caused by
medications such as dopamine, Dobutamine or Digitalis. A decreased
SVI can be caused by CHF, late septic shock, beta-blockers or an
MI.
[0051] The term "stroke volume" (SV) refers to the amount of blood
pumped by the heart per cardiac cycle, and is measured in
milliliters per beat. A decreased SV may indicate impaired cardiac
contractility or valve dysfunction and may result in heart failure.
An increased SV can be caused by an increase in circulating volume
or an increase in inotropy.
[0052] The term "systemic vascular resistance" (SVR refers to the
measurement of resistance or impediment of the systemic vascular
bed to blood flow. An increase in SVR can be caused by
vasoconstrictors, hypovolemia or late septic shock. A decrease in
SVR can be caused by early septic shock, vasodilators, morphine,
nitrates or hypercarbia.
[0053] A "microgram" (.mu.g) is 1 millionth of a gram, i.e.,
10.sup.-6 grams.
[0054] A "nanogram" (ng) is 1 billionth of a gram, i.e., 10.sup.-9
grams.
[0055] A "picogram" pg) is 1 trillionth of a gram, i.e., 10.sup.-12
grams.
[0056] Table 1 provides normal values for the above-described
hemodynamic parameters.
TABLE-US-00001 TABLE 1 Hemodynamic Parameter Normal Value Blood
Pressure Systolic (SBP) 90-140 mm Hg Diastolic (DBP) 60-90 mm Hg
Mean Arterial Pressure (MAP) 70-100 mm Hg Cardiac Index (CI) 2.5-4
L/min/m.sup.2 Cardiac Output (CO) 4-8 L/min Central Venous Pressure
(CVP) 2-6 mm Hg Pulmonary Artery Pressure (PA) Systolic: 20-30 mm
Hg (PAS) Diastolic: 8-12 mm Hg (PAD) Mean: 25 mm Hg (PAM) Pulmonary
Capillary Wedge Pressure 4-12 mm Hg (PWCP) Pulmonary Vascular
Resistance (PVR) 37-250 dynes/sec/cm.sup.3 Right Ventricular
Pressure (RV) Systolic-20-30 mm Hg Diastolic 0-5 mm Hg Stroke Index
(SI) 25-45 mL/m.sup.2 Systemic Vascular Resistance (SVR) 800-1200
dynes/sec/cm.sup.3
[0057] Various sources of CGRP may be used in the methods of this
invention. For example, synthetic CGRP may be obtained using an
automatic peptide synthesizer according to well known methods. One
method for synthesizing the CGRP is the well known Merrifield
method (see, Merrifield, R. B., J. Am. Chem. Soc. 85:2149 (1963)
and Merrifield, R. B., Science, 232:341 (1986), which are
specifically incorporated herein by reference). Human CGRP also may
be obtained from commercial sources, such as Peninsula Laboratory
(Belmont, Calif.), Bachem Biosciences, Inc. (King of Prussia, Pa.)
and Sigma Chemicals (St. Louis, Mo.). Commercial grade human CGRP
is not marketed for human use (since this grade is not GMP/GLP
grade); therefore, commercially available human CGRP may be used in
the present invention only if it is purified and sterilized so that
it is fit for human use. Genetically engineered human CGRP can also
be used in the present invention. Similar results also could be
achieved using a CGRP analogue or an analogue based on the CGRP
"receptor structure." These include peptide-based analogues, as
well as peptide-mimetic analogues. Accordingly, analogs that
function similarly to CGRP are considered to be equivalents of CGRP
for purposes of this invention. Animal-derived CGRP is biologically
active and thus could be used in the present invention; however, as
a practical matter, animal-derived CGRP presents allergy and
autoimmune problems and therefore is preferably avoided.
[0058] Other forms of CGRP that are suitable for use in the methods
of this invention are pharmaceutically acceptable prodrugs of CGRP.
A "pharmaceutically acceptable prodrug" is a compound that may be
converted under physiological conditions or by solvolysis to the
specified compound or to a pharmaceutically acceptable salt of such
compound. Prodrugs of CGRP may be identified using routine
techniques known in the art. Prodrugs include compounds wherein an
amino acid residue, or a polypeptide chain of two or more (e.g.,
two, three or four) amino acid residues is covalently joined
through an amide or ester bond to a free amino, hydroxy or
carboxylic acid group of compounds of the present invention.
Additional types of prodrugs are also encompassed. For instance,
free carboxyl groups can be derivatized as amides or alkyl esters.
Free hydroxy groups may be derivatized using groups including but
not limited to hemisuccinates, phosphate esters,
dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, as
outlined in Advanced Drug Delivery Reviews 1996, 19, 115. Carbamate
prodrugs of hydroxy and amino-groups are also included, as are
carbonate prodrugs, sulfonate esters and sulfate esters of hydroxy
groups. Derivatization of hydroxy groups as (acyloxy)methyl and
(acyloxy)ethyl ethers wherein the acyl group may be an alkyl ester,
optionally substituted with groups including but not limited to
ether, amine and carboxylic acid functionalities, or where the acyl
group is an amino acid ester as described above, are also
encompassed. Prodrugs of this type are described in J. Med. Chem.
1996, 39, 10. Free amines can also be derivatized as amides,
sulfonamides or phosphonamides. All of these prodrug moieties may
incorporate groups including but not limited to ether, amine and
carboxylic acid functionalities. Other examples of such prodrug
derivatives are described in a) Design of Prodrugs, edited by H.
Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 42, p.
309-396, edited by K. Widder, et al. (Academic Press, 1985); b) A
Textbook of Drug Design and Development, edited by
Krogsgaard-Larsen and H. Bundgaard, Chapter 5. "Design and
Application of Prodrugs", by H. Bundgaard p. 113-191 (1991); c) H.
Bundgaard, Advanced Drug Delivery Reviews, 8:1-38 (1992); d) H.
Bundgaard, et al., J. Pharmaceutical Sciences, 77:285 (1988); and
e) N. Kakeya, et al., Chem. Pharm. Bull., 32:692 (1984), each of
which is specifically incorporated herein by reference.
[0059] When administered in controlled dosages, CGRP has pronounced
cardiovascular benefits, including vasodilation, ischemic
cardioprotection, reduction in infarction size due to heart attack,
inhibition of platelet aggregation and smooth muscle cell
proliferation to potentially reduce the incidence of restenosis,
increased renal function, and overall increased efficiency of
cardiovascular functions. CGRP also plays a role in regulating
inotropy, chronotropy, microvascular permeability, vascular tone,
and angiogenesis.
[0060] As stated, CGRP has significant advantages over conventional
drug treatments. First, CGRP does not produce the potentially
dangerous side effects, toxicity and tolerance associated with
conventional cardiovascular drugs such as nitroglycerin, Dobutamine
and Natrecor. In fact, CGRP has been reported to down-regulate
immune response via inhibition of cytokine release and has been
safely administered to immunosuppressed subjects without the
induction of sensitivity. Second, since CGRP possesses multiple
hemodynamic benefits, it potentially reduces or eliminates the need
for drug cocktails to maintain specific hemodynamic functions.
Third, more than 20 years of research on the potency, safety and
efficacy of the drug in animals and humans have demonstrated the
cardiovascular benefits of CGRP and have shown that CGRP exhibits
virtually no side effects or tolerance when administered
systemically.
[0061] In general, there are four goals in treating HF patients:
(1) treating the symptoms, (2) slowing the progression of cardiac
dysfunction, (3) decreasing length of hospital stay, and (4)
increasing the time between hospitalization, all while minimizing
health care costs. It is believed that the methods for the
treatment or prophylaxis of HF according to this invention will
achieve one or more of these goals.
[0062] In order to use CGRP for the therapeutic treatment
(including prophylactic treatment) of mammals including humans
according to the methods of this invention, it is normally
formulated in accordance with standard pharmaceutical practice as a
pharmaceutical composition. According to this aspect of the
invention there is provided a pharmaceutical composition comprising
CGRP in association with a pharmaceutically acceptable diluent or
carrier, wherein the CGRP is present in an amount for effective
treating or preventing HF and/or for improving renal function.
[0063] CGRP can be administered to a patient by any available and
effective delivery system including, but not limited to,
parenteral, transdermal, intranasal, sublingual, transmucosal,
intra-arterial, or intradermal modes of administration in dosage
unit formulations containing conventional nontoxic pharmaceutically
acceptable carriers, adjuvants, and vehicles as desired, such as a
depot or a controlled release formulation.
[0064] For example, CGRP or a pharmaceutically acceptable
formulation thereof may be formulated for parenteral
administration, e.g., for intravenous, subcutaneous, or
intramuscular injection. For an injectable formulation, a dose of
CGRP may be combined with a sterile aqueous solution which is
preferably isotonic with the blood of the patient. Such a
formulation may be prepared by dissolving a solid active ingredient
in water containing physiologically-compatible substances such as
sodium chloride, glycine, and the like, and having a buffered pH
compatible with physiological conditions so as to produce an
aqueous solution, and then rendering the solution sterile by,
methods known in the art. The formulations may be present in unit
or multi-dose containers, such as sealed ampules or vials. The
formulation may be delivered by any mode of injection, including,
without limitation, epifascial, intracutaneous, intramuscular,
intravascular, intravenous, parenchymatous, subcutaneous, oral or
nasal preparations (see, for example, U.S. Pat. No. 5,958,877,
which is specifically incorporated herein by reference).
[0065] Pharmaceutical compositions may also be in the form of a
sterile injectable aqueous or oily suspension, which may be
formulated according to known procedures using one or more
appropriate dispersing or wetting agents and suspending agents. A
sterile injectable preparation may also be a sterile injectable
solution or suspension in a non-toxic parenterally-acceptable
diluent or solvent, for example a solution in 1,3-butanediol.
[0066] In any of the embodiments of this invention, CGRP is
optionally conjugated to a biocompatible, biodegradable polymer to
form a conjugate. As used herein, the term "conjugate" refers to a
CGRP molecule covalently or noncovalently coupled to one or more
polymers. Examples of polymers include, but are not limited to,
biological polymers (e.g., polysaccharides, polyamides,
pharmacologically inert nucleotide components, etc.), derivatives
of biological polymers, and non-biological polymers. Specific
examples include, are not limited to, poly(alkylene glycols such as
poly(ethylene glycol) (PEG), poly-lactic acid (ALA), poly-glycolic
acid, poly(.epsilon.-caprolactone), poly(.beta.-hydroxybutyrate),
poly(.beta.-hydroxyvalerate), polydioxanone, poly(malic acid),
poly(tartronic acid), poly(ortho esters), polyanhydrides,
polycyanoacrylates, poly(phosphoesters), polyphosphazenes,
hyaluronidate, polysulfones, polyacrylamides, polymethacrylate,
chimeric recombinant elastin-silk protein (Protein Polymers, Inc.)
and collagen (Matrix Pharmaceuticals, Inc) (for detailed discussion
of the above mentioned polymers, see, Park, K. et al. (1993)
Biodegradable Hydrogels for Drug Delivery. Technomic Publishing
Co., Inc., Lancaster, Pa.). The polymers noted above can optionally
be crosslinked to modify the utility thereof, such as to render the
compounds more or less water soluble. Numerous crosslinking agents
are useful, including diols and higher polyols, polyamines,
polycarboxylic acids, polyisocyanates and the like.
[0067] CGRP can be conjugated to any of the above-described
polymers using conventional methods known to those skilled in the
art, wherein the conjugation is performed under conditions which do
not substantially reduce the pharmacological activity of CGRP. For
example, CGRP can be covalently coupled to the polymer directly
through reaction of a reactive group on the CGRP with a reactive
group of the polymer. The term "reactive group" refers to a
chemical moiety which is attached to CGRP or the polymer or bonds
in the polymer which participate in the chemical reaction between
the components involved, i.e., CGRP and the polymer. Examples of
reactive groups include without limitation hydroxyl, carboxyl,
amine, amide, carbon-carbon double and triple bonds, epoxy groups,
halogen or other leaving groups and the like. Alternatively, CGRP
can be coupled to the polymer through a linking group. The term
"linking group" is not limited to molecules per se, and refers to
compounds, molecules and molecular fragments that can react with
the polymer, monomers and CGRP to attach CGRP to the polymer. As
such, the linking groups include compounds and the like with more
than one reactive group, preferably two or three reactive
groups.
[0068] Parenteral Administration
[0069] According to one embodiment, this invention provides a
method of treating BF in a patient comprising administering CGRP or
a pharmaceutically acceptable composition thereof to the patient at
a rate between about 50 and 500 ng/min for a time between 30
minutes and 8 hours per day for as many days as needed to provide
symptomatic relief, prevent exacerbation of symptoms, and/or
prevent and/or delay progression of the disease state of heart
failure in said patient. For example, CGRP may be continuously or
intermittently administered for a period of time between about 24
and 48 hours, or as a bolus dose. If CGRP is administered two or
more times intermittently each day, lower doses, e.g., 0.8 to 10
ng/min can be administered.
[0070] Treatment is continued as needed to provide symptomatic
relief, prevent exacerbation of symptoms, and/or prevent and/or
delay progression of the disease state of heart failure in said
patient, or until it is no longer well tolerated by the patient, or
until a physician terminates treatment. For example, a physician
may monitor one or more symptoms of HF, renal blood flow,
glomerular filtration rates, and/or serum levels of urea and
creatinine in a patient being treated with CGRP according to this
invention and, upon observing attenuation of one or more symptoms
of HF for a period of time, conclude that the patient can sustain
the positive effects of the above-described treatment without
further administration of CGRP for a period of time. If necessary,
the patient may then return at a later point in time for additional
treatment as needed.
[0071] According to another embodiment, this invention provides a
method of treating HF in a patient comprising administering CGRP to
the patient at a rate between about 500 and 600 ng/min for period
between about 8 hours per day for at least three consecutive days
or several times per week as needed to provide symptomatic relief,
prevent exacerbation of symptoms, and/or prevent and/or delay
progression of the disease state of heart failure in the patient.
This treatment may be provided as outpatient therapy to prevent
exacerbation of the heart failure and to enhance the quality of
life in the patient.
[0072] As used herein, "day" means a 24-hour period. Thus, for
example, "for at least three consecutive days" means for at least a
72-hour period. During or after the treatment, a physician may
monitor one or more symptoms of HF, renal blood flow, glomerular
filtration rates, and/or serum levels of urea or creatinine in the
patient and, upon observing an improvement in one or more of the
parameters for a period of time, conclude that the patient can
sustain the positive effects of the treatment without further
administration of CGRP for a period of time.
[0073] According to another embodiment, this invention provides a
method of treating HF in a patient comprising administering CGRP to
the patient at a rate between about 50 and 400 ng/min over a period
of up to 8 hours per day for each day of hospitalization of the
patient or as needed. In certain cases the patient may require
higher doses, for example up to 2 .mu.g/min over the same time
period.
[0074] Once treatment with CGRP according to any of the methods of
this invention has achieved the desired results, e.g., symptomatic
relief, prevent exacerbation of symptoms, and/or prevent and/or
delay progression of the disease state of heart failure, the
patient can then receive maintenance therapy if desired. For
example, a lower dose of CGRP, e.g., less than 10 ng/min, can be
administered to the patient for maintenance therapy by any suitable
route including, but not limited to, injection, intravenous
administration, etc. In one embodiment, the delivery regime can be
designed to deliver between CGRP at a rate between about 0.8 to 10
ng/min for a desired period of time, such as over a period of 3, 6
or 9 months.
[0075] Because CGRP therapy according to any of the methods of this
invention prevents further damage from ischemic injury and promotes
the healing process, it can also be used to delay or preclude
further exacerbation of a heart condition into a more serious and
progressive diseases such as HF. Thus, each of the above-described
methods may also be used as a prophylactic treatment to prevent or
slow the progression of early stages of HF to more advanced stages.
That is, once treatment with CGRP according to any of the methods
of this invention has achieved the desired results, the patient can
optionally receive maintenance therapy thereafter. For example, one
embodiment of this invention for providing maintenance therapy to a
patient with a heart, condition comprises providing a lower dose of
CGRP, e.g., less than 10 ng/min, to the patient for maintenance
therapy by any suitable route including, but not limited to,
injection, intravenous administration, controlled release
administration, etc. In one embodiment, the delivery system can be
designed to deliver between CGRP at a rate between about 0.8 to 10
ng/min for a desired period of time, such as over a period of 3, 6
or 9 months. In an alternative embodiment, the patient can receive
long-term, low dose, maintenance administration of CGRP from a
controlled release formulation.
[0076] In addition, it is known that a patient that has suffered a
myocardial infarction (MI) will likely suffer another MI in the
future. Thus, a patient having an MI can be treated with an initial
dose of CGRP according to any of the methods of this invention
until one or more symptoms of HF has diminished, and subsequently
can be put on a CGRP maintenance dosing regime. The maintenance
regime can also be given to a post-MI patient that was initially
treated for MI by means other than CGRP, and can also be used for
HF patients that have not yet suffered an MI as a means to slow the
progression of HF into the more advanced stages or to prevent or
reduce the risk of MI in patients with advanced HF.
[0077] This invention further provides methods for improving renal
function in a patient suffering from diminished renal function
comprising administering CGRP according to any of the
above-describe dosing regimes for treating HF. As used herein, the
term "improved renal function" includes increased glomerular
filtration, increased renal blood flow and decreased serum levels
of urea and creatinine.
[0078] If necessary, CGRP can be administered according to the
methods of this invention either alone or in combination with at
least one other agent including, but not limited to,
anti-proliferative agents, anti-clotting agents, vasodilators,
diuretics, beta-blockers calcium ion channel blockers, blood
thinners, cardiotonics, ACE inhibitors, anti-inflammatories,
antioxidants, and/or gene therapeutics. When used in combination
with other agents, CGRP and the agent can be administered
separately (either simultaneously or separately in any order) or in
admixture. In one embodiment, when CGRP and at least one other
agent are administered as separate components, they are
administered to the patient at about the same time. "About the same
time" means that within about thirty minutes of administering one
compound (e.g., CGRP) to the patient, the other compound (e.g., an
anti-proliferative or anti-clotting agent) is administered to the
patient. "About the same time" also includes concomitant or
simultaneous administration of the compounds.
[0079] Controlled Release Administration
[0080] Another aspect of this invention provides methods of
treating HF and/or renal failure by delivering CGRP to a patient as
a controlled releases formulation. As used herein, the term
"controlled" or "sustained" release of CGRP includes continuous or
discontinuous, linear or non-linear release of CGRP. There are many
advantages for a controlled release formulation of CGRP. Among
these are the convenience of a single injection for the patient,
avoidance of peaks and valleys in systemic CGRP concentration which
can be associated with repeated injections, the potential to reduce
the overall dosage of CGRP, delayed progression of HF,
cardioprotection, and the potential to enhance the pharmacological
effects of CGRP. A lower, sustained dose can also prevent adverse
affects that: are occasionally observed with infusion therapy. In
addition to significantly reducing the cost of care, controlled
release drug therapy can free the patient from repeated treatment
or hospitalization thus offering the patient greater flexibility
and improving patient compliance. A controlled release formulation
of CGRP also provides an opportunity to use CGRP in a manner not
previously exploited or considered, such as a maintenance
therapeutic for patients that have suffered an MI or in patients at
high risk of suffering an MI, such as Stage B, C and D heart
failure patients.
[0081] 1. Controlled Release Implant
[0082] One embodiment of a controlled release composition of this
invention comprises suitable for use in treating or preventing HF
comprises a flowable composition that forms a biodegradable implant
comprising CGRP in situ. This invention further comprises a kit
that includes the flowable composition. The flowable composition
comprises a biodegradable, biocompatible thermoplastic polymer or
copolymer in combination with a suitable polar solvent and CGRP.
The thermoplastic polymers or copolymers are substantially
insoluble in water and body fluid and are biodegradable and/or
bioerodible within the body of an animal. The flowable composition
is administered for example as a liquid or gel to a tissue or
bodily fluid wherein the implant (i.e., a polymer matrix) is formed
in situ, and CGRP is subsequently released from the matrix by
diffusion or dissolution from within the polymer matrix and/or by
the degradation of the polymeric matrix. The composition is
biocompatible and the polymer matrix does not cause substantial
tissue irritation or necrosis at the implant site. Examples of
biocompatible, biodegradable controlled release polymer
formulations suitable for purposes of this invention are provided
in U.S. Pat. Nos. RE 37,950 E, 6,143,314 and 6,582,080 B2, which
are specifically incorporated herein by reference.
[0083] More specifically, a flowable thermoplastic polymeric
composition of this invention comprises a thermoplastic polymer or
copolymer dissolved in a pharmaceutically-acceptable organic
solvent that is miscible to dispersible in an aqueous medium to
provide a polymeric solution, and CGRP or a CGRP conjugate either
dissolved to form a homogeneous solution or dispersed to form a
suspension or a dispersion of CGRP within the polymeric solution.
When the polymer solution is placed in an aqueous environment, such
as a bodily tissue or fluid which typically surround tissues or
organs in an organism, the organic solvent dissipates or disperses
into the aqueous or body fluid. Concurrently, the polymer
precipitates or coagulates to form a solid matrix or implant and
CGRP becomes trapped or encapsulated within the polymeric matrix as
the implant solidifies. Once the solid implant is formed, CGRP is
released from the solid matrix by diffusion or dissolution from
within the polymeric matrix and/or by the degradation of the
polymeric matrix.
[0084] Preferably, the flowable composition is a liquid, gel, paste
or putty suitable for injection in a patient. As used herein,
"flowable" refers to the ability of the composition to be
administered by any suitable means into the body of a patient. For
example, the composition can be injected into a specific site in
the patient with the use of a syringe and puncture needle or placed
into accessible tissue sites through a cannula. The ability of the
composition to be injected into a patient will typically depend
upon the viscosity of the composition. The composition will
therefore have a suitable viscosity such that the composition can
be forced through the medium (e.g., syringe) into the body of a
patient. As used herein, a "liquid" is a substance that undergoes
continuous deformation under a shearing stress (Concise Chemical
and Technical Dictionary, 4.sup.th Enlarged Ed., Chemical
Publishing Co., Inc., p. 707, N.Y., N.Y. (1986)). The term "gel"
refers a substance having a gelatinous, jelly-like, or colloidal
property (Concise Chemical and Technical Dictionary, 4.sup.th
Enlarged Ed., Chemical Publishing Co., Inc., p. 567, N.Y., N.Y.
(1986)).
[0085] The term "biodegradable" means that the polymer matrix will
degrade over time, for example by the action of enzymes, by
hydrolytic action and/or by other similar mechanisms in the
patient's body. By "bioerodible," it is meant that the polymer
matrix will erode or degrade over time due, at least in part, to
contact with substances found in the surrounding tissue fluids or
cellular action. By "bioabsorbable" it is meant that the polymer
matrix will be broken down and absorbed within the human body, for
example, by a cell or tissue. "Biocompatible" means that the
polymer, the solvent and the resulting polymer matrix will not
elicit an adverse biologic response in the patient.
[0086] A thermoplastic composition is provided in which a
biodegradable polymer and CGRP are dissolved in a biocompatible
solvent to form a flowable composition, which can then be
administered, for example, via a syringe and puncture needle or a
catheter. Any suitable biodegradable, bioabsorbable, and/or
bioerodible thermoplastic polymer can be employed, provided the
biodegradable thermoplastic polymer is at least substantially
insoluble in aqueous medium or body fluid. Suitable biodegradable
thermoplastic polymers are disclosed, e.g., in U.S. Pat. Nos.
5,324,519; 4,938,763; 5,702,716; 5,744,153; and 5,990,194, each of
which is specifically incorporated herein by reference. The
thermoplastic polymers can be made form a variety of monomers which
form linear or branched polymer chains or monomeric units joined
together by linking groups such as esters, amides urethanes, etc.
According to one embodiment, some fraction of one of these starting
monomers will be at least trifunctional, and provides at lest some
branching of the resulting polymer chain. Examples of suitable
biodegradable polymers include, but are not limited to,
polylactides, polyglycolides, polycaprolactones, polyanhydrides,
polyamides, polyorthoesters, polyurethanes, polyesteramides,
polydioxanones, polyacetals, polyketals, polycarbonates,
polyorthocarbonates, polyphosphazenes, polyhydroxybutyrates,
polyhydroxyvalerates, polyalkylene oxalates, polyacrylates,
polyalkylene succinates, poly(malic acid), poly(amino acids) and
copolymers, terpolymers, cellulose diacetate and ethylene vinyl
alcohol copolymers, and combinations thereof.
[0087] The type, molecular weight, and amount of biodegradable
thermoplastic polymer present in the composition will typically
depend upon the desired properties of the controlled release
implant. For example, the type, molecular weight, and amount of
biodegradable thermoplastic polymer can influence the length of
time in which CGRP is released from the controlled release implant.
Specifically, in one embodiment of the present invention, the
composition can be used to formulate a one month delivery system of
CGRP. In such an embodiment, the biodegradable thermoplastic
polymer can preferably be 50/50 poly (DL-lactide-co-glycolide), can
be present in about 30 wt. % to about 40 wt. % of the composition,
and can have an average molecular weight of about 12,000 to about
45,000. Alternatively, in another embodiment the composition can be
used to formulate a three month delivery system of CGRP. In such an
embodiment, the biodegradable thermoplastic polyester can
preferably be 75/25 poly (DL-lactide-co-glycolide), can be present
in about 40 wt. % to about 50 wt. % of the composition, and can
have an average molecular weight of about 15,000 to about
24,000.
[0088] The molecular weight of the polymer used in the present
invention can affect the rate of CGRP release in situ from the
implant. As the molecular weight of the polymer increases, the rate
of CGRP release from the system decreases. This phenomenon can be
advantageously used in the formulation of systems for the
controlled release of CGRP. For relatively quick release of CGRP,
low molecular weight polymers can be chosen to provide the desired
release rate. For release of a CGRP over a relatively long period
of time, a higher polymer molecular weight can be chosen.
Accordingly, a polymer system can be produced with an optimum
polymer molecular weight range for the release of CGRP over a
selected length of time. The molecular weight of a polymer can be
varied by any of a variety of methods known to persons skilled in
the art.
[0089] The particular biocompatible polymer employed is not
critical and is selected relative to the viscosity of the resulting
polymer solution, the solubility of the biocompatible polymer in
the biocompatible solvent, the desired release rate, and the like.
Such factors are well known to persons skilled in the art. The
biodegradable thermoplastic polyester is preferably present in
about 30 wt. % to about 50 wt. % of the flowable composition.
Preferably, the biodegradable thermoplastic polyester has an
average molecular weight of about 12,000 to about 45,000 and more
preferably from about 15,000 to about 30,000.
[0090] The concentration of the polymer dissolved in the various
solvents will differ depending upon the type of polymer and its
molecular weight, and these factors can be varied to obtain optimum
injection efficiency. CGRP is added to the polymer solution where
it is either dissolved to form a homogenous solution or dispersed
to form a suspension or a dispersion of drug within the polymeric
solution.
[0091] Suitable organic solvents for preparing the thermoplastic
polymer composition are those that are biocompatible,
pharmaceutically acceptable, and able to diffuse into in aqueous or
body fluids so that the flowable composition coagulates or
solidifies. The organic solvent is capable of diffusing,
dispersing, or leaching from the composition in situ into aqueous
tissue or body fluid of the implant site. Examples of suitable
solvents include substituted heterocyclic compounds such as
N-methyl-2-pyrrolidone and 2 pyrrolidone; esters of carbonic acid
and alkyl alcohols such as propylene carbonate, ethylene carbonate
and dimethyl carbonate; alkyl esters of mono-, di-, and
tricarboxylic acids such as 2-ethyoxyethyl acetate, ethyl acetate,
methyl acetate, ethyl lactate, ethyl butyrate, diethyl malonate,
diethyl glutonate, tributyl citrate, diethyl succinate, tributyrin,
isopropyl myristate, dimethyl adipate, dimethyl succinate, dimethyl
oxalate, dimethyl citrate, triethyl citrate, acetyl tributyl
citrate, glyceryl triacetate; alkyl ketones such as acetone and
methyl ethyl ketone; alcohols such as solketal, glycerol formal,
and glycofurol; dialkylamides such as dimethylformamide,
dimethylacetamide; dimethylsulfoxide (DMSO) and dimethylsulfone;
tetrahydrofuran; lactones such as .epsilon.-caprolactone and
butyrolactone; cyclic alkyl amides such as caprolactam; aromatic
amides such as N,N-dimethyl-m-toluamide and
1-dodecylazacycloheptan-2-one; and mixtures and combinations
thereof. Preferred solvents include polar aprotic solvents such as
N-methyl-2-pyrrolidone, 2-pyrrolidone, N-dimethyl formamide,
dimethylsulfoxide, caprolactam, triacetin, ethyl lactate, propylene
carbonate, solketal, glycerol formal, glycofurol, or any
combination thereof.
[0092] The solvent can be present in any suitable amount, provided
the solvent is miscible to dispersible in aqueous medium or body
fluid. The type and amount of biocompatible solvent present in the
composition will typically depend upon the desired properties of
the controlled release implant. For example, the type and amount of
biocompatible solvent can influence the length of time in which the
CGRP is released from the controlled release polymer matrix.
Preferably, the solvent is present in about 45-70 wt. % of the
polymeric composition. Specifically, in one embodiment of the
present invention, the composition can be used to formulate a one
month delivery system of CGRP. In such an embodiment, the
biocompatible solvent can preferably be N-methyl-2-pyrrolidone and
can preferably present in about 60 wt. % to about 70 wt. % of the
composition. Alternatively, in another embodiment of the present
invention, the composition can be used to formulate a three month
delivery system of CGRP. In such an embodiment, the biocompatible
solvent can preferably be N-methyl-2-pyrrolidone and can preferably
present in about 50 wt. % to about 60 wt. % of the composition.
[0093] The solubility of the biodegradable thermoplastic polymers
in the various solvents will differ depending upon their
crystallinity, their hydrophilicity, hydrogen-bonding, bonding, and
molecular weight. Thus, not all of the biodegradable thermoplastic
polymers will be soluble in the same solvent, and each
biodegradable thermoplastic polymer or copolymer will have its
appropriate solvent.
[0094] A method for forming a flowable polymeric composition
includes mixing, in any order, a biodegradable thermoplastic
polyester, a biocompatible solvent, and CGRP. These ingredients,
their properties, and preferred amounts are as disclosed above. The
mixing is performed for a sufficient period of time effective to
form the flowable composition for use as a controlled release
implant. Preferably, the biocompatible thermoplastic polyester and
the biocompatible solvent are mixed together to form a mixture and
the mixture is then combined with CGRP to form the flowable
composition. If necessary, gentle heating and stirring can be used
to effect dissolution of the biocompatible polymer into the
biocompatible solvent.
[0095] The amount of CGRP incorporated into the polymeric
composition depends upon several factors, including but not limited
to the desired release profile, the concentration of CGRP required
for a biological effect, and the length of time that CGRP has to be
released for effective treatment. There is no critical upper limit
on the amount of CGRP incorporated into the polymer solution except
for that of an acceptable solution or dispersion viscosity for
injection through a syringe needle. The lower limit of CGRP
incorporated into the delivery system is dependent simply upon the
activity of the CGRP and the length of time needed for
treatment.
[0096] The release of CGRP from the solid polymer matrices
(implants) will follow the same general rules for release of a drug
from a monolithic polymeric device. The release of CGRP can be
affected by the size of the implant (i.e., the amount of polymer
composition administered to the patient), the loading of CGRP
within the implant, the permeability factors involving CGRP and the
particular polymer, and the degradation of the polymer. Depending
upon the amount of CGRP selected for delivery, the above parameters
can be adjusted by one skilled in the art of drug delivery to give
the desired rate and duration of release. Thus, the flowable
composition can be designed to produce an implant that will release
CGRP over a targeted period from days to months.
[0097] The amount of flowable composition administered will
typically depend upon the desired properties of the controlled
release implant. For example, the amount of flowable composition
can influence the length of time in which CGRP is released from the
controlled release implant.
[0098] It is desirable with any of the controlled release systems
or formulations described herein that CGRP is delivered to the
patient at a rate and in an amount that will achieve blood plasma
levels necessary to provide symptomatic relief, e.g., by
attenuating one or more symptoms of HF. The following are examples
of minimum and maximum IV infusion rates, cumulative daily dose and
plasma levels required to bring about the fall range of hemodynamic
benefits that CGRP induces without any serious side effects in
hemodynamically compromised patients. Minimal and transient facial
flushing may be observed, but dosages are very well tolerated in IV
infusions.
[0099] 1. Minimum infusion rate and daily dose delivered to cause
attenuation of one or more symptoms of HF for a patient weighing 70
kg: 0.0008 .mu.g/kg/min.times.70 kg.times.1440 minutes 80.64
.mu.g/day.
[0100] 2. Maximum infusion rate and daily dose delivered to cause
attenuation of one or more symptoms of HF for a patient weighing 70
kg: 0.016 .mu.g/kg/min.times.70 kg.times.1440 minutes 1.6
mg/day.
[0101] It is well within the skill of persons skilled in the art to
determine the amount of CGRP to be loaded into a particular drug
delivery system to provide the desired steady state plasma levels
of CGRP as described herein to provide relief of one or more
symptoms of HF or to improve one or more hemodynamic properties
according to the methods of this invention.
[0102] The following is an example of the amount of CGRP to include
in a transdermal delivery system that will deliver CGRP across the
skin at a rate suitable to maintain a steady state plasma level of
157.+-.26 .mu.g/mL, which has been found to produce profoundly
beneficial hemodynamic responses including increased cardiac
output, decreased ventricular filling pressures, pulmonary and
systemic arterial pressures, vascular resistance, increased
glomerular filtration, and renal blood flow. If it is assumed that
a transdermal delivery system can deliver 25% of the loaded CGRP
across the skin, then in order to deliver a total drug load similar
to that delivered by an IV dose of 560 ng/min (0.008 .mu.g/kg/min)
over 8-24 hours (i.e., delivery of 288-806 .mu.g CGRP) the total
drug load required for the transdermal delivery system would be
approximately 1.152-3.456 mg. Polymer matrix systems capable of
delivering 100% of the drug at a rate suitable to maintain similar
steady state plasma levels would require a total drug load four
times less than transdermal systems, i.e., 0.288-0.806 mg. Peak
plasma levels of CGRP at 157.+-.26 pg/ml are obtained in the first
60 minutes. In a preferred embodiment the peak level is maintained
for 8-24 hours.
[0103] Tables 2 and 3 show examples of the amount of CGRP to be
added to a flowable composition and the corresponding injection
volumes in order to produce implants that will provide the
indicated delivery rates over 7, 30, 60, 90, 120 or 180 days and
maintain steady state plasma levels of CGRP up to 157.+-.26 pg/mL.
In Tables 2 and 3, delivery rates and CGRP loads are provided for
compositions that will produce implants in situ comprising 5 wt. %
and 15 wt. % CGRP, respectively.
TABLE-US-00002 TABLE 2 Thermoplastic polymer compositions
comprising 5% CGRP Delivery Duration of release (Days) Rate 7 30 90
120 180 0.0008 Drug Load (mg) 0.56 2.42 7.26 9.68 14.52
.mu.g/kg/min Injection (cc) 0.01 0.05 0.15 0.19 0.29 0.0032 Drug
Load (mg) 2.26 9.69 29.07 38.76 58.14 .mu.g/kg/min Injection (cc)
0.04 0.19 0.58 0.77 1.16 0.008 Drug Load (mg) 5.64 24.18 72.54
96.72 145.08 .mu.g/kg/min Injection (cc) 0.11 0.48 1.45 1.93 2.90
0.016 Drug Load (mg) 11.27 48.30 144.90 193.20 289.80 .mu.g/kg/min
Injection (cc) 0.22 0.97 2.90 3.86 5.80
TABLE-US-00003 TABLE 3 Thermoplastic polymer compositions
comprising 15% CGRP Duration of release (Days) Delivery Rate 7 30
90 120 180 0.0008 .mu.g/kg/min Drug Load (mg) 0.56 2.42 7.26 9.68
14.52 Injection (cc) 0.004 0.02 0.05 0.065 0.097 0.0032
.mu.g/kg/min Drug Load (mg) 2.26 9.69 29.07 38.76 58.14 Injection
(cc) 0.02 0.07 0.19 0.26 0.39 0.008 .mu.g/kg/min Drug Load (mg)
5.64 24.18 72.54 96.72 145.08 Injection (cc) 0.04 0.16 0.48 0.64
0.97 0.016 .mu.g/kg/min Drug Load (mg) 11.27 48.30 144.90 193.20
289.80 Injection (cc) 0.08 0.32 0.97 1.29 1.93
[0104] For example, in one embodiment of the present invention, a
polymeric composition comprising 5 wt. % CGRP (i.e., 5.64 mg CGRP)
can be formulated to produce a polymer matrix in situ that will
deliver CGRP at circulating plasma levels of CGRP up to 157.+-.26
pg/ mL or deliver CGRP at a rate of 0.008 .mu.g g/kg/min over a
period of 7 days when about 0.11 mL of this composition is
administered to a patient (Table 2). Alternatively, if it is
desired to have the CGRP delivered at circulating plasma levels of
CGRP of 157.+-.26 pg/mL or a rate of 0.008 .mu.g/kg/min over a
period of 180 days, a composition comprising 15 wt. % CGRP (i.e.,
145.08 mg CGRP) can be prepared and about 0.97 mL of this
composition is administered to the patient (Table 3). In a similar
fashion, other compositions can be prepared according to the
examples shown in Tables 2 and 3 to provide the desired circulating
plasma levels of CGRP and delivery rate over the targeted time
period. It is to be understood that the formulations in Tables 2
and 3 are provide as examples to illustrate the invention, and it
would be well within the skill of persons of ordinary skill in the
art to design other formulations that would yield different
delivery rates over different time periods.
[0105] The compositions of this invention can be delivered directly
to a target site and can be designed to provide continuous release
of CGRP over a targeted time period so as to reduce the frequency
of drug administration. In general, a solid implant or matrix is
formed upon dispensing the flowable polymeric composition either
into a tissue or onto the surface of a tissue which is surrounded
by an aqueous medium. The composition can be delivered to a
patient's tissue or bodily fluid by any convenient technique. For
example, the thermoplastic polymeric solution can be placed in a
syringe and injected through a needle into a patient's body, i.e.,
in the desired tissue site or bodily fluid. Upon discharge of the
composition from the needle into the tissue or fluid, the solvent
dissipates or diffuses away from the polymer and into the
surrounding fluid, resulting in the precipitation of the
biocompatible polymer which precipitate forms a coherent mass or
polymer matrix. The polymer matrix can adhere to its surrounding
tissue or bone by mechanical forces and can assume the shape of its
surrounding cavity and conform to the irregular surface of the
tissue. The implant will biograde over time and does not require
removal when CGRP is depleted.
[0106] In certain instances, formation of the solid matrix from the
flowable delivery system is not instantaneous. For example, the
process can occur over a period of minutes to several hours. During
this period, the rate of diffusion of CGRP from the coagulating
polymeric composition may be much more rapid than the rate of
release that occurs from the subsequently formed solid matrix.
"Initial burst" refers to the release of a CGRP from the polymeric
composition during the first 24 hours after the polymeric
composition is contacted with an aqueous fluid. This initial
"burst" of CGRP that is released during polymer matrix formation
may result in the loss or release of a large amount of the active
agent. Therefore, in certain embodiments the thermoplastic polymer
composition can further comprise a polymeric controlled release
additive that substantially reduces the "initial burst" of CGRP
released from the polymeric composition during the initial 24 hours
after implantation. The use of such an additive is described in
U.S. Pat. No. 6,143,314, which is specifically incorporated herein
by reference. As used herein, the term "substantially reduces"
means a decrease of at least 15%, and preferably between about 15%
to about 70%, of CGRP that is released from the polymeric
composition compared to a composition without the additive.
Examples of suitable controlled release additives include
thermoplastic polymers having poly(lactide-co-glycolide) (PLG)
moieties and polyethylene glycol (PEG) moieties. In one embodiment,
the controlled release additive is a
poly(lactide-co-glycolide)/polyethylene glycol (PLG/PEG) block
copolymer. The polymeric controlled release additive is present in
the polymeric composition in an amount effective to reduce the
initial burst of biologically active agent released from the
polymeric composition during the first 24 hours after implantation.
Preferably, the polymeric composition includes about 1 wt. % to
about 50 wt. %, more preferably about 2 wt. % to about 20 wt. % of
the polymeric controlled release additive.
[0107] The solid matrix is capable of biodegradation, bioerosion
and/or bioabsorption within the implant site of the patient or
animal, and will slowly biodegrade within the body and will release
CGRP contained within its matrix at a controlled rate until
depleted. Generally, the polymer matrix will breakdown over a
period from about 1 week to about 12 months. The release of CGRP
can be affected by the size and shape of the polymer matrix, the
loading of drug within the polymer matrix, the permeability factors
involving CGRP and the particular polymer, and the degradation of
the polymer. The above parameters can be adjusted by one skilled in
the art of drug delivery to give the desired rate and duration of
release (see for example Tables 2 and 3).
[0108] The polymeric CGRP solution can be placed anywhere within
the body, including tissue sites such as soft tissue (e.g., muscle
or fat), hard tissue (e.g., bone), or a cavity such as the
periodontal, oral, vaginal, rectal, or nasal cavity. As used
herein, the term "tissue site" includes any tissues in an organism.
A tissue site is typically surrounded by an aqueous or body fluid
such as subcutaneous tissue, interstitial fluid, blood, serum,
cerebrospinal fluid or peritoneal fluid.
[0109] A suitable polymeric gel for use in this embodiment
comprises ABA-or BAB-type block copolymers, where the A-blocks are
relatively hydrophobic A polymer blocks comprising a biodegradable
polyester, and the B-blocks are relatively hydrophilic B polymer
blocks comprising polyethylene glycol (PEG). The A block is-
preferably a biodegradable polyester synthesized from monomers
selected from the group consisting of D,L-lactide, D-lactide,
L-lactide, D,L-lactic acid, D-lactic acid, L-lactic acid,
glycolide, glycolic acid, .epsilon.-caprolactone,
.epsilon.-hydroxyhexanoic .lamda.-hydroxybutyric acid,
.delta.-valerolactone, .delta.-hydroxyvaleric acid, hydroxybutyric
acids, malic acid, and copolymers thereof, and the B block is PEG.
The polymeric gel is preferably biodegradable and exhibits water
solubility at low temperatures and undergoes reversible thermal
gelation at physiological mammalian body temperatures. Furthermore,
these polymeric gels are biocompatible and capable of releasing
CGRP entrained within its matrix over time and in a controlled
manner. The polymeric gel may be prepared as disclosed in U.S. Pat.
No. 6,201,012, which is incorporated herein by reference.
[0110] Other suitable polymers include in situ formed hydrogels
prepared from thermosensitive block copolymers. Such block
copolymers undergo reversion between gel and sol under certain
conditions. The gel-sol transition temperature is generally above
room temperature, which depends on the composition of the gel, as
well as on the chemical structure and molecular weight of PEG or
PEG copolymers. The polymer is a poly(ethylene glycol), a
derivative thereof, or a copolymer that reacts with the
poly(ethylene glycol) segment. The polymer can also be
poly(propylene glycol) (PPG) or other poly(alkylene glycols).
Higher molecular weight poly(ethylene glycol) is also called
poly(ethylene oxide) (PEO). Poly(ethylene glycol) block copolymers
with poly(propylene oxide) (PPO), including an pluronic polymers
(Poloxamers) may also be used. Different molecular weight of each
segment, and weight ratio of the blocks, and different sequences
may be used such as PEO-PPO-PEO (Pluronic), PPO-PEO-PPO
(Pluronic-R), PEO-PPO, etc.
[0111] Suitable polymers useful in the invention include PLURONIC
(BASF Corp.) surfactant which is a group of poly(ethylene
oxide)-polypropylene oxide)poly(ethylene oxide) triblock copolymers
also known as poloxamers. The PEG block at both ends is able to
complex with alpha-cyclodextrin, just like the PEG molecules.
PLURONIC polymers have unique surfactant abilities and extremely
low toxicity and immunogenic responses. These products have low
acute oral and dermal toxicity and low potential for causing
irritation or sensitization, and the general chronic and subchronic
toxicity is low. In fact, PLURONIC polymers are among a small
number of surfactants that have been approved by the FDA for direct
use in medical applications and as food additives (BASF (1990)
Pluronic & Tetronic Surfactants, BASF Co., Mount Olive, N.J.).
Recently, several PLURONIC polymers have been found to enhance the
therapeutic effect of drugs (March, K. L., et al., Hum. Gene
Therapy 6(1): 41-53, 1995).
[0112] The hydrogel-based injectable composition may be prepared in
any suitable manner. Generally, CGRP in aqueous solution is
combined with the poly(ethylene glycol) component. The mixture is
cooled, generally to a temperature of 0.degree. C. to 25.degree. C.
The resulting product is a white viscous hydrogel.
[0113] 2. Films
[0114] This invention further provides a prophylaxis for or method
of treating HF and/or renal failure comprising administering
biodegradable, biocompatible polymeric film comprising CGRP to a
patient. The polymeric films are thin compared to their length and
breadth. The films typically have a uniform selected thickness
between about 60 micrometers and about 5 mm. Films of between about
600 micrometers and 1 mm and between about 1 mm and about 5 mm
thick, as well as films between about 60 micrometers and about 1000
micrometers; and between about 60 and about 300 micrometers are
useful in the manufacture of therapeutic implants for insertion
into a patient's body. The films can be administered to the patient
in a manner similar to methods used in adhesion surgeries. For
example, a CGRP film formulation can be sprayed or dropped onto a
tissue site during surgery, or a formed film can be placed over the
selected tissue site. In an alternative embodiment, the film can be
used as sustained release coating on a medical device such as a
stent.
[0115] Either biodegradable or nonbiodegradable polymers may be
used to fabricate implants in which the CGRP is uniformly
distributed throughout the polymer matrix A number of suitable
biodegradable polymers for use in making the biodegradable films of
this invention are known to the art, including polyanhydrides and
aliphatic polyesters, preferably polylactic acid (PLA),
polyglycolic acid (PGA) and mixtures and copolymers thereof, more
preferably 50:50 copolymers of PLA:PGA and most preferably 75:25
copolymers of PLA:PGA. Single enantiomers of PLA may also be used,
preferably L-PLA, either alone or in combination with PGA.
Polycarbonates, polyfumarates and caprolactones may also be used to
make the implants of this invention.
[0116] A plasticizer may be incorporated in the biodegradable film
to make it softer and more pliable for applications where direct
contact with a contoured surface is desired.
[0117] The polymeric films of this invention can be formed and used
as flat sheets, or can be formed into three-dimensional
conformations or "shells" molded to fit the contours of the tissue
site into which the film is inserted.
[0118] To make the polymeric films of this invention, a suitable
polymeric material is selected, depending on the degradation time
desired for the film. Selection of such polymeric materials is
known to the art. A lower molecular weight, e.g. around 20,000
daltons, 50:50 or 55:45 PLA:PGA copolymer is used when a shorter
degradation time is desired. To ensure a selected degradation time,
the molecular weights and compositions may be varied as known to
the art.
[0119] Polymeric films of this invention may be made by dissolving
the selected polymeric material in a solvent known to the art,
e.g., acetone, chloroform or methylene chloride, using about 20 mL
solvent per gram of polymer. The solution is then degassed,
preferably under gentle vacuum to remove dissolved air and poured
onto a surface, preferably a flat non-stick surface such as BYTAC
(Trademark of Norton Performance Plastics, Akron, Ohio) non-stick
coated adhesive-backed aluminum foil, glass or TEFLON.TM..
Non-stick polymer. The solution is then dried, preferably
air-dried, until it is no longer tacky and the liquid appears to be
gone. The known density of the polymer may be used to
back-calculate the volume of solution needed to produce a film of
the desired thickness.
[0120] Films may also be made by heat pressing and melt
forming/drawing methods known to the art. For example, thicker
films can be pressed to form thinner films, and can be drawn out
after heating and pulled over forms of the desired shapes, or
pulled against a mold by vacuum pressure.
[0121] The amount of CGRP to be incorporated into the polymeric
films of this invention is an amount effective to show a measurable
effect in treating of preventing HF and/or renal failure. CGRP can
be incorporated into the film by various techniques such as by
solution methods, suspension methods, or melt pressing.
[0122] Solid CGRP implants can also be made into various shapes
other than films by injection molding or extrusion techniques. For
example, the implant can comprise a core material such as
ethylene/vinyl acetate copolymer, and a vinyl acetate content of
20% by weight or more and which functions as a matrix for CGRP, in
a quantity which is sufficient for a controlled release of CGRP,
and a membrane which encases the core material and also consists of
EVA material and an acetate content of less than 20% by weight. The
implant can be obtained, for example, by means of a co-axial
extrusion process, a method in which the two EVA polymers are
extruded co-axially with the aid of a co-axial extrusion head. The
co-axial extrusion process is art known per se so that it will not
be gone into further within the scope of this description.
[0123] 3. Encapsulated CGRP
[0124] Yet another CGRP controlled release formulation according to
this invention comprises very small capsules which can be
administered, for example by injection, into body tissue of fluids.
Accordingly, this invention further provides a method of treating
HF by administering capsules comprising CGRP, and a kit comprising
said capsules. The capsules include an encapsulating layer which
surrounds CGRP or comprises CGRP dispersed throughout the
encapsulating layer. After injection, the -encapsulating layer
degrades or dissolves, and CGRP is released within the heart. CGRP
can also diffuse through the encapsulating layer. The encapsulating
layer may be made from various materials including biodegradable
polymers in the form of microspheres, or from standard vesicle
forming lipids which form liposomes and micelles. Such sustained
release CGRP capsules are useful for treatment or prophylaxis of HE
and/or renal failure. Both biodegradable and nonbiodegradable
polymers may be used to prepare formulations in which CGRP is
encapsulated within a polymer matrix and surrounded by a
rate-controlling membrane.
[0125] a. Microspheres
[0126] One embodiment of CGRP-containing capsules comprises solid
microparticles formed of the combination of biodegradable polymers
with CGRP loadings that yield a sustained release over a period of
one day to at least one week, when administered orally,
transmucosally, topically or by injection. The microparticles have
different diameters depending on their route of administration. For
example, microparticles administered by injection have diameters
sufficiently small to pass through a needle, in a size range of
between 10 and 100 microns. Orally administered microparticles are
preferably less than 10 microns in diameter to facilitate uptake by
the small intestine. The microspheres can contain from less than
0.01% by weight up to approximately 50% by weight CGRP.
[0127] As used herein, "micro" refers to a particle having a
diameter of from nanometers to micrometers. Microspheres are solid
spherical particles; microparticles are particles of irregular or
non-spherical shape. A microsphere may have an outer coating of a
different composition than the material originally used to form the
microsphere. Thus, the term "microsphere" as used herein
-encompasses microparticles, microspheres and microcapsules.
[0128] Polymers that can be used to form the microspheres include,
but are not limited to, biodegradable polymers such as
poly(lactic-co-glycolic acid) (PLG), poly(lactic acid) (PLA),
poly(caprolactone), polycarbonates, polyamides, polyanhydrides,
polyamino acids, polyortho esters, polyacetals, polycyanoacrylates
and degradable polyurethanes, and copolymers thereof. Almost any
type of polymer can be used provided the appropriate solvent and
non-solvent are found which have the desired melting points.
[0129] Biodegradable microspheres can be prepared using any of the
methods developed for making microspheres for drug delivery, for
example, as described by Mathiowitz and Langer (J. Controlled
Release, 5:13-22 (1987)); Mathiowitz, et al. (Reactive Polymers,
6:275-283 (1987)); and Mathiowitz, et al. (J. Appl. Polymer Sci.,
35:755-774 (1988)), the teachings of which are incorporated herein.
The selection of the method depends on the polymer selection, the
size, external morphology, and crystallinity that is desired, as
described, for example, by Mathiowitz, et al. (Scanning Microscopy,
4:329-340 (1990)); Mathiowitz, et al. (J. Appl. Polymer Sci.,
45:125-134 (1992)); and Benita, et al. (J. Pharm. Sci. 73:1721-1724
(1984)), the teachings of which are incorporated herein. Methods
include solvent evaporation, phase separation, spray drying, and
hot melt encapsulation. U.S. Pat. Nos. 3,773,919; 3,737,337;
3,523,906; 4,272,398; 5,019,400; 5,271,961 and 6,403,114 are
representative of methods for making microspheres, each of which is
specifically incorporated herein by reference. U.S. Pat. No.
5,019,400, which is incorporated herein by reference, describes the
Prolease.RTM. process in which microspheres can be formed in a size
suitable for injection through a 26-gauge needle, (less than 50
micrometers in diameter). The process described in U.S. Pat. No.
5,019,400 has the advantage of achieving drug encapsulation in the
absence of water at very low temperatures. These conditions are
particularly suitable for fragile macromolecules such as proteins,
where maintaining stability is a concern. Microparticles can be
formed by either a continuous freezing and extraction process or by
a batch process wherein a batch of frozen microdroplets is formed
in a first step, and then in a separate second step, the frozen
microdroplets in the batch are extracted to form microparticles.
U.S. Pat. No. 6,403,114 describes a method of preparing
microspheres in commercial batch sizes, and U.S. Pat. No. 5,271,961
describes a continuous method of preparing microspheres. Each of
these patents are incorporated herein by reference
[0130] In general, microspheres can be prepared by combining CGRP,
the polymer and a solvent to form a droplet, and then removing the
solvent to yield microspheres that are hardened, dried, and
collected as a free-flowing powder. Prior to administration to the
patient, the powder is suspended in a diluent and then injected
into the patient. Release of CGRP from the microsphere is governed
by diffusion of CGRP through the polymer matrix and by
biodegradation of the polymer. The release kinetics can be
modulated through a number of formulation and fabrication variables
including polymer characteristics and the addition of excipients
and release modifiers. In solvent evaporation, described in U.S.
Pat. No. 4,272,398, which is incorporated herein by reference, the
polymer is dissolved in a volatile organic solvent. The CGRP,
either in soluble form or dispersed as fine particles, is added to
the polymer solution, and the mixture is suspended in an aqueous
phase that contains a surface active agent such as poly(vinyl
alcohol). The resulting emulsion is stirred until most of the
organic solvent evaporates, leaving solid microspheres. After
loading the solution with CGRP, the solution is suspended in
distilled water containing 1% (w/y) poly(vinyl alcohol), after
which the solvent is evaporated and resulting microspheres are
dried overnight in a lyophilizer. Microspheres with different sizes
(1-1000 microns) and morphologies can be obtained by this method
which is useful for relatively stable polymers such as polyesters
and polystyrene.
[0131] Polymer hydrolysis is accelerated at acidic or basic pH's
and thus the inclusion of acidic or basic excipients can be used to
modulate the polymer erosion or degradation rate. The excipients
can be added as particulates, can be mixed with the incorporated
CGRP or can be dissolved within the polymer.
[0132] Degradation modulators can also be added to the
microparticle formulation, and the amount added is based on weight
relative to the polymer weight. They can be added to the
formulation as a separate phase (i.e., as particulates) or can be
codissolved in the polymer phase depending on the compound. In all
cases the amount of enhancer added is preferably between 0.1 and
thirty percent (w/w, polymer). Types of degradation modulators
include inorganic acids such as ammonium sulfate and ammonium
chloride, organic acids such as citric acid, benzoic acids,
heparin, and ascorbic acid, inorganic bases such as sodium
carbonate, potassium carbonate, calcium carbonate, zinc carbonate,
and zinc hydroxide, and organic bases such as protamine sulfate,
sperinine, choline, ethanolamine, diethanolamine, and
triethanolamine and surfactants such as Tween.TM. and
Pluronic.TM..
[0133] Stabilizers can be also added to the formulations to
maintain the potency of CGRP depending on the duration of release.
Stabilizers include carbohydrates, amino acids, fatty acids, and
surfactants and are known to those skilled in the art. In addition,
excipients which modify the solubility of CGRP such as salts
complexing agents (albumin, protamine) can be used to control the
release rate of the protein from the microparticles.
[0134] In one embodiment for the treatment or prophylaxis of HF
and/or renal failure, the patient is administered CGRP incorporated
in microparticles which degrade over a period of 1 of 2 months. The
microparticles preferably range in size from 10 to 60 microns, and
can be injected using a puncture needle with the aid of a
suspension media. One example of a suspension media comprises 3%
methyl cellulose, 4% mannitol, and 0.1% Tween.TM.80.
[0135] In a further embodiment, microparticles containing CGRP can
be embedded in a gel matrix as described in U.S. Pat. No.
6,589,549, which is incorporated herein by reference. In this
embodiment, CGRP (alone or in combination with one or more
additional agents) may be located in the microparticle alone or
both in the microparticle and the gel matrix. The microparticle-gel
delivery system can release CGRP over a prolonged period of time at
a relatively constant rate. The release profile of the system can
be modified by altering the microparticle and/or the gel
composition. After injection, the gel sets and localizes the
microparticle suspended in it. CGRP encapsulated in the
microparticle must be released from the microparticle before
traveling through the gel matrix and entering the biological
system. Therefore, the immediate release, or the burst, associated
with microparticle delivery systems can be reduced and modulated.
Since the release rates of CGRP from these two systems can be quite
different, embedding microparticles in the gel phase offers
additional modulation and economical use of CGRP. The benefits
include higher bioavailability and longer duration of action than
either system when used alone. Moreover, the combined system can
improve the safety of microparticle dosage form. A suitable
polymeric gel for use in this embodiment comprises ABA-or BAB-type
block copolymers, where the A-blocks are relatively hydrophobic A
polymer blocks comprising a biodegradable polyester, and the
B-blocks are relatively hydrophilic B polymer blocks comprising
polyethylene glycol (PEG). The A block is preferably a
biodegradable polyester synthesized from monomers selected from the
group consisting of D,L-lactide, D-lactide, L-lactide, D,L-lactic
acid, D-lactic acid, L-lactic acid, glycolide, glycolic acids
.epsilon.-caprolactone, .epsilon.-hydroxyhexanoic
.lamda.-hydroxybutyric acid, .delta.-valerolactone,
.delta.-hydroxyvaleric acid, hydroxybutyric acids, malic acid, and
copolymers thereof, and the B block is PEG. The polymeric gel is
preferably biodegradable and exhibits water solubility at low
temperatures and undergoes reversible thermal gelation at
physiological mammalian body temperatures. Furthermore, these
polymeric gels are biocompatible and capable of releasing CGRP
entrained within its matrix over time and in a controlled manner.
The polymeric gel may be prepared as disclosed in U.S. Pat. No.
6,201,072, which is incorporated herein by reference.
[0136] b. Solid Implants
[0137] Solid implants made by injection molding or extrusion method
similar to that used to manufacture Norplant.TM., a product brand
and a trademark of Leiras Co., which is based on a non-degradable
polymeric material. In this embodiment, a definitely formed, device
constructed of silicone rubber which is implanted into the body by
a surgical operation, and it is removed therefrom in a similar
manner after a defined time when the active component has been
released and diffused to the body. Any of the polymeric materials
utilized for the construction of implantable devices may be used in
the practice of the invention. A broad class of silicone elastomers
can be used to form the silicone-elastomer drug matrix. Suitable
silicone elastomers in accordance with the present invention
include SILASTIC.TM. and R-2602 RTV silicone elastomer available
from Nusil Silicone Technology (Carpinteria, Calif.). The silicone
elastomers can be catalyzed so that polymerization and formation of
the core is accomplished at room temperature. The core may also be
formed by heat curable core material. Generally, the silicone
implantable depots are constructed of polydimethylsilicone (PDMS).
See, for example, U.S. Pat. Nos. 4,957,119 and 5,088,505, which are
incorporated herein by reference. A typical material is
dimethylpolysiloxane (Silgel.TM. 601, Wacker Chemie GmbH), an
addition cross-linking two-component composition of nine pats of
component A and one part of component B.
Dimethyldiphenylpolysiloxane, dimethylpolysiloxanol or silicone
copolymers may also be employed. Other suitable polymeric materials
are the porous, ethylene/vinyl acetate copolymers which have been
utilized to construct depots for the implantable release of
hydrophilic biologically active substances such as proteins through
the pores thereof. Biodegradable polymers may also be used to form
the solid implants using extrusion or injection molding
processes.
[0138] c. Liposomes
[0139] Another method of delivering CGRP to a patient is
accomplished with encapsulation by liposomes, wherein CGRP may be
sequestered in the liposome membrane or may be encapsulated in the
aqueous interior of the vesicle. The term "liposome" refers to an
approximately spherically shaped bilayer structure, or vesicle,
comprised of a natural or synthetic phospholipid membrane or
membranes that contain two hydrophobic tails consisting of fatty
acid chains, and sometimes other membrane components such as
cholesterol and protein, which can act as a physical reservoir for
CGRP. Upon exposure to water, the phospholipid molecules
spontaneously align to form sphercal, bilayer membranes with the
lipophilic ends of the molecules in each layer associated in the
center of the membrane and the opposing polar ends forming the
respective inner and outer surface of the bilayer membrane(s).
Thus, each side of the membrane presents a hydrophilic surface
while the interior of the membrane comprises a lipophilic medium.
These membranes may be arranged in a series of concentric,
spherical membranes separated by thin strata of water around an
internal aqueous space. These multilamellar vesicles (MLV) can be
converted into small or unilamellar vesicles (UV), with the
application of a shearing force. Liposomes are characterized
according to size and number of membrane bilayers. Vesicle
diameters can be large (>200 nm) or small (<50 nm) and the
bilayer can have unilamellar, oligolamellar, or multilamellar
membrane.
[0140] The selection of lipids is generally guided by
considerations of liposome size and ease of liposome sizing, and
lipid and CGRP release rates from the site of liposome delivery.
Typically, the major phospholipid components in the liposomes are
phosphatidylcholine (PC), phosphatidylglycerol (PG), phosphatidyl
serine (PS), phosphatidylinositol (PI) or egg yolk lecithin (EYL).
PC, PG, PS, and PI having a variety of acyl chains groups or
varying chain lengths are commercially available, or may be
isolated or synthesized by known techniques.
[0141] Current methods of drug delivery by liposomes require that
the liposome carrier will ultimately become permeable and release
the encapsulated drug. This can be accomplished in a passive manner
in which the liposome membrane degrades over time through the
action of agents in the body. Every liposome composition will have
a characteristic half-life in the circulation or at other sites in
the body. In contrast to passive drug release, active drug release
involves using an agent to induce a permeability change in the
liposome vesicle. In addition, liposome membranes can be made which
become destabilized when the environment becomes destabilized near
the liposome membrane (Proc. Nat. Acad. Sci., 84:7851 (1987);
Biochemistry, 28:9508, (1989)). For example, when liposomes are
endocytosed by a target cell they can be routed to acidic endosomes
which will destabilize the liposomes and result in drug release.
Alternatively, the liposome membrane can be chemically modified
such that an enzyme is placed as a coating on the membrane which
slowly destabilizes the liposome (The FASEB Journal, 4:2544
(1990)). It is also well known that lipid components of liposomes
promote peroxidative and free radical reactions which cause
progressive degradation of the liposomes, and has been described in
U.S. Pat. No. 4,797,285. The extent of free radical damage can be
reduced by the addition of a protective agent such as a lipophilic
free radical quencher is added to the lipid components in preparing
the liposomes. Such protectors of liposome are also described in
U.S. Pat. No. 5,190,761, which also describes methods and
references for standard liposome preparation and sizing by a number
of techniques. Protectors of liposomal integrity will increase the
time course of delivery and provide for increased transit time
within the target tissue.
[0142] Liposomes for use in the present invention can be prepared
by any of the various techniques presently known in the art.
Typically, they are prepared from a phospholipid, for example,
distearoyl phosphatidylcholine, and may include other materials
such as neutral lipids, for example, cholesterol, and also surface
modifiers such as positively charged (e.g., sterylamine or
aminomannose or aminomannitol derivatives of cholesterol) or
negatively charged (e.g., diacetyl phosphate, phosphatidyl
glycerol) compounds. Multilamellar liposomes can be formed by
conventional techniques, that is, by depositing a selected lipid on
the inside wall of a suitable container or vessel by dissolving the
lipid in an appropriate solvent, and then evaporating the solvent
to leave a thin film on the inside of the vessel or by spray
drying. An aqueous phase is then added to the vessel with a
swirling or vortexing motion which results in the formation of
MLVs. UVs can then be formed by homogenization, sonication or
extrusion (through filters)of MLV's. In addition, UVs can be formed
by detergent removal techniques
[0143] The liposomes containing CGRP can be delivered within
biodegradable microdrug delivery systems such as larger more stable
liposomes or other fully encapsulated controlled release system,
such as a biodegradable impermeable polymer coatings. The time
course of release is governed then by the additive time delay of
the barriers that separate CGRP from the host, as well as their
combined transport pathways. Microsphere delivery systems could
also be used.
[0144] 4. CGRP Conjugates
[0145] A further aspect of this invention includes CGRP conjugated
to polymers, and to methods of treating HF and/or renal failure by
administering a CGRP conjugate to a patient. It is known that many
potentially therapeutic proteins have been found to have a short
half life in the blood serum. For the most part, proteins are
cleared from the serum through the kidneys. Small molecules that
normally would be excreted through the kidneys are maintained in
the blood stream if their size is increased by attaching a
biocompatible polymer such as a PEG derivative. Proteins and other
substances that create an immune response when injected can be
hidden to some degree from the immune system by coupling of a
polymer to the protein. Accordingly, another embodiment of this
invention comprises a method of treating HF by administering a
conjugate comprising CGRP coupled to a biocompatible,
non-immunogenic polymer. As used herein, the term "conjugate"
refers to a CGRP molecule covalently or noncovalently coupled to
one or more polymers. These conjugates are substantially
non-immunogenic and retain at least 75%, preferably 85%, and more
preferably 95% or more of the activity of unmodified CGRP.
[0146] Examples of polymers that can be coupled to CGRP include,
but not limited to, biological polymers (e.g., polysaccharides,
polyamides, pharmacologically inert nucleotide components, etc.),
and derivatives of biological polymers, or non-biological polymers.
Specific examples include poly(alkylene glycols) such as
poly(ethylene glycol) MPEG), poly-lactic acid (PLA), poly-glycolic
acid, poly(.epsilon.-caprolactone), poly(.beta.-hydroxybutyrate),
poly(.beta.-hydroxyvalerate), polydioxanone, poly(malic acid),
poly(tartronic acid), poly(ortho esters), polyanhydrides,
polycyanoacrylates, poly(phosphoesters), polyphosphazenes,
hyaluronidate, polysulfones, polyacrylamides, polymethacrylate,
chimeric recombinant elastin-silk protein (Protein Polymers, Inc.)
and collagen (Matrix Pharmaceuticals, Inc.). In a preferred
embodiment CGRP is conjugated to PEG or a polysaccharide.
[0147] As used herein the term "PEG" includes to straight or
branched polyethylene glycol oligomer and monomers (PEG subunits)
and also includes polyethylene glycol oligomers that have been
modified to include groups which do not eliminate the amphiphilic
properties of such oligomer, e.g. without limitation, alkyl, lower
alkyl, aryl, amino-alkyl and amino-aryl. The term "PEG subunit"
refers to a single polyethylene glycol unit, i.e.,
--(CH.sub.2CH.sub.20)--.
[0148] Reactive sites that form the loci for attachment of polymers
to CGRP are dictated by the protein's structure. Many polymers
react with free primary amino groups or thiol groups of the
polypeptide. Covalent attachment of the polymers to CGRP may be
accomplished by known chemical synthesis techniques. In one
embodiment of the invention, CGRP may be conjugated via a
biologically stable, nontoxic, covalent linkage to one or more
strands of PEG. Such linkages may include urethane (carbamate)
linkages, secondary amine linkages, and amide linkages. Various
activated PEGs suitable for such conjugation are available
commercially from Shearwater Polymers, Huntsville, Ala.
[0149] 5. Transdermal Delivery
[0150] CGRP may also be administered to a patient via transdermal
delivery devices, patches, electrophoretic devices, bandages and
the like. Such transdermal patches may be used to provide
continuous or discontinuous infusion of CGRP in controlled amounts.
The construction and use of transdermal patches for the delivery of
pharmaceutical agents is well known in the art. See, for example,
U.S. Pat. No. 5,023,252, the disclosure of which is herein
incorporated by reference. Such patches may be constructed for
continuous, pulsatile, or on-demand delivery of CGRP. For example,
a dose of CGRP or a pharmaceutically acceptable composition thereof
may be combined with skin penetration enhancers including, but not
limited to, oleic acid, oleyl alcohol, long chain fatty acids,
propylene glycol, polyethylene glycol, isopropanol, ethoxydiglycol,
sodium xylene sulfonate, ethanol, N-methylpyrrolidone, laurocapram,
alkanecarboxylic acids, dimethylsulfoxide, polar lipids,
N-methyl-2-pyrrolidone, and the like, which increase the
permeability of the skin to the dose of CGRP and permit the dose of
CGRP to penetrate through the skin and into the bloodstream. CGRP
or a pharmaceutically acceptable composition thereof may be
combined one or more agents including, but not limited to,
alcohols, moisturizers, humectants, oils, emulsifiers, thickeners,
thinners, surface active agents, fragrances, preservatives,
antioxidants, vitamins, or minerals. CGRP or a pharmaceutically
acceptable composition thereof may also be combined with a
polymeric substance including, but not limited to, ethylcellulose,
hydroxypropyl cellulose, ethylene/vinylacetate, polyvinyl
pyrrolidone, and the like, to provide the composition in gel form,
which may be dissolved in solvent such as methylene chloride,
evaporated to the desired viscosity, and then applied to backing
material to provide a patch. The backing can be any of the
conventional materials such as polyethylene, ethyl-vinyl acetate
copolymer, polyurethane and the like.
[0151] 6. Transmucosal Delivery
[0152] CGRP may also be administered transmucosally, i.e., to and
across a mucosal surface, for example, for the treatment of angina.
Transmucosal administration of a source of CGRP or a
pharmaceutically acceptable composition thereof can be accomplished
generally by contacting an intact mucous membrane with a source of
CGRP or a pharmaceutically acceptable composition thereof, and
maintaining the source in contact with the mucous membrane for a
sufficient time period to induce the desired therapeutic effect.
Preferably CGRP or a pharmaceutically acceptable composition
thereof is administered to the oral or nasal mucosa such as the
buccal mucosa, the sublingual mucosa, the sinuidal mucosa, the gum,
or the inner lip. Particularly, the source of CGRP is any
preparation usable in oral, nasal, sinuidal, rectal or vaginal
cavities that can be formulated using conventional techniques well
known in the art. For example, the preparation can be a buccal
tablet, a sublingual tablet, a spray, and the like that dissolves
or disintegrates, delivering drug into the mouth of the patient. A
spray or drops can also be used to deliver the CGRP or a
pharmaceutically acceptable composition thereof to nasal or
sinuidal cavities. The preparation may or may not deliver the drug
in a sustained fashion. Examples for manufacturing such
preparations are disclosed, for example, in U.S. Pat. No.
4,764,378, which is specifically incorporated herein by reference.
The preparation can also be a syrup that adheres to the mucous
membrane. Suitable mucoadhesives include those well known in the
art such as polyacrylic acids, preferably having the molecular
weight between from about 450,000 to about 4,000,000, e.g. ,
Carbopol.TM. 934P; sodium carboxymethylcellulose (NaCMC),
hydroxypropylmethylcellulose (HPMC), e.g. Methocel.TM. K100, and
hydroxypropylcellulose.
[0153] The transmucosal preparation can also be in the form of a
bandage, patch, and the like that contains the drug and adheres to
a mucosal surface. A mucoadhesive preparation is one that upon
contact with intact mucous membrane adheres to the mucous membrane
for a sufficient time period to induce the desired therapeutic
effect. Suitable transmucosal patches are described for example in
PCT Publication WO 93/23011, which is specifically incorporated
herein by reference. A suitable patch may comprise a backing which
can be any flexible film that prevents bulk fluid flow and provides
a barrier for to loss of the drug from the patch. The backing can
be any conventional material such as polyethylene, ethyl-vinyl
acetate copolymer, polyurethane and the like. In a patch involving
a matrix which is not itself a mucoadhesive, the drug-containing
matrix can be coupled with a mucoadhesive component (such as a
mucoadhesive described above) in order that the patch may be
retained on the mucosal surface. Suitable configurations include a
patch or device wherein the matrix has a smaller periphery than the
backing layer such that a portion of the backing layer extends
outward from the periphery of the matrix. A mucoadhesive layer
covers the outward extending portion of the backing layer such that
the underside of the backing layer carries a layer of mucoadhesive
around its periphery. The backing and the peripheral ring of
mucoadhesive taken together form a reservoir which contains a
drug-containing matrix (e.g. a tablet, gel or powder). It may be
desirable to incorporate a barrier element between the matrix and
the mucoadhesive in order to isolate the mucoadhesive from the
matrix. The barrier element is preferably substantially impermeable
to water and to the mucosal fluids that will be present at intended
site of adhesion. A patch or device having such barrier element can
be hydrated only through a surface that is in contact with the
mucosa, and it is not hydrated via the reservoir. Such patches can
be prepared by general methods well known to those skilled in the
art. The preparation can also be a gel or film comprising a
mucoadhesive matrix as described for example in PCT Publication WO
96/30013, which is specifically incorporated herein by
reference.
[0154] 7. Implantable Pumps
[0155] In another embodiment, CGRP can be suitably administered
using an implantable pump, which is particularly applicable for
outpatient treatment. For example, a constant rate pump may be used
to provide a constant, unchanging delivery of CGRP over a period of
time. Alternatively, a programmable, variable rate pump may be used
if changes to the infusion rate are desired. Constant rate and
programmable pumps are well know in the art and need not be
described further.
[0156] CGRP may also be released or delivered from an implantable
osmotic mini-pump such as that described in U.S. Pat. Nos.
5,728,396, 5,985,305, 6,358,247, and 6,544,252, the disclosures of
which are specifically incorporated herein in their entirety. The
release rate from an osmotic mini-pump may be modulated with a
microporous, fast-response gel disposed in the release orifice for
controlled release or targeted deliver of CGRP. Osmotic pumps are
preferred in that they are much smaller than the constant rate and
programmable pumps.
[0157] In one embodiment, the osmotic pump comprises a miniature
drug-dispensing system that operates like a miniature syringe and
releases minute quantities of concentrated CGRP formulations in a
continuous, consistent flow over months or years. The system is
implanted under the skin and can be as small as 4 mm OD.times.44 mm
in length or smaller. Such a system is sold under the trademark
DUROS.RTM. by ALZA Corporation. In brief, such an osmotic delivery
system comprises a capsule having an interior that contains the
CGRP and ah osmotic agent, a semi-permeable body that permits
liquid to permeate through the body to the osmotic agent, and a
piston located within the interior of the capsule that defines a
movable seal within the interior that separated the osmotic agent
from the CGRP.
[0158] Augmentation of Current HF Therapies
[0159] A further aspect of this invention provides a method of
treating HF by administering CGRP according to any of the methods
disclosed herein to augment current HF therapies. CGRP can be
administered according to any of the dosing regimes of this
invention together with one or more addition drugs for HF, wherein
CGRP and the additional drug(s) can be administered together,
separately and simultaneously, or separately in any order.
[0160] Acute Myocardial Infarction
[0161] In the treatment of acute MI, physicians take. aggressive
action to restore blood flow to the heart to minimize permanent
ischemic damage. These treatments take the form of vasodilators
(nitroglycerin) and antithrombolytics. (streptokinase, tPA), and
platelet aggregation inhibitors (gpIIb/IIIa) in the attempt to
dilate the coronary arteries and dissolve the thrombus, and inhibit
platelet aggregation. If treatment is successful in restoring blood
flow, the patient may be sent to recover in the CCU or go to the
catheterization lab for an angioplasty or stenting procedure to
open any remaining occlusions. However, the ischemic event itself
causes generation of free radicals, and this process is potentiated
when the vessels are re-opened and blood flow restored, which
results in further tissue damage. In this setting, CGRP therapy
administered alone or in conjunction with other therapeutic
interventions according to any of the methods of this invention,
particularly the infusion methods, would augment the current
therapies such as antithrombolytics by elevating the therapeutic
benefits of these drugs. The cardioprotective benefits of CGRP when
infused at the initial stages of evaluation and treatment would
provide levels of CGRP suitable to minimize reperfusion injury when
interventional therapy is initiated, and thus maximize positive
acute and long-term recovery outcomes.
[0162] Accordingly, this invention further provides a method of
counteracting ischemia due to myocardial infarction in a patient,
comprising delivering to said patient an amount of CGRP effective
to provide cardioprotection, reduction in infarction size,
reduction in reperfusion injury, symptomatic relief, and/or prevent
exacerbation of symptoms, wherein said CGRP is delivered to said
patient as a controlled release composition.
[0163] Percutaneous Translumenal Coronary Angioplasty (PTCA) and
Stenting
[0164] If antithrombolytic therapy is ineffectual in the emergency
room, or if it is determined that elective PTCA intervention is
required to restore blood flow, CGRP infusion therapy already in
process in the emergency room or started in the catheterization lab
would provide the same reperfusion benefits as those described
above when blood flow is restored to the ischemic tissues.
Additional benefits in the catheterization lab would be realized
when CGRP infusion therapy locally dilates coronary blood vessels,
decreases the incidence of vasospasms and no-reflow during
procedures, increases renal blood flow, and assists in preventing
platelet aggregation and smooth muscle cell proliferation at the
acute time points (<24 hours) following PTCA. Currently,
Reopro.RTM. or Integrillin.RTM. is administered in advance or
during PTCA procedures to halt platelet aggregation and reduce the
incidence of restenosis in the long-term (>48 hours). CGRP
infusion therapy would augment these current restenosis therapies
by elevating the therapeutic benefits of preventing reperfusion
injury, as well as inhibiting platelet aggregation and smooth
muscle cell proliferation in the acute-term (<24, hours).
[0165] Coronary Artery Bypass Surgery (CABG)
[0166] Whether CABG is performed as an emergency procedure or as
elective surgery, CGRP infusion therapy would provide all of the
benefits stated above with respect to acute MI treatment and PTCA
procedures. As a result, a CABG procedure could potentially
experience even great positive outcomes and fewer acute-term
complications.
[0167] Coronary Care Unit (CCU) Recovery
[0168] CGRP infusion therapy in CCU patients would maximize the
ability of CGRP to reduce infarction size and promote cardiac
tissue salvage. Whether the therapy was initiated in the emergency
room, the cauterization lab, the operating room, or the CCU,
recovery and healing process will begin in the CCU where CGRP can
be administered over the course of several days, and the long-term
benefits of CGRP infusion therapy will realized.
[0169] Kits
[0170] The present invention also provides pharmaceutical kits for
treating HF and/or improving renal function, comprising one or more
containers comprising one or more CGRP compositions of this
invention. Such kits can also include additional drugs or
therapeutics (e.g., antiproliferative or anti-clotting agents, or
other compounds used to treat cardiovascular diseases and the like)
for co-use with CGRP for treatment or prevention of HF and/or for
improving renal failure. In this embodiment, the CGRP and the drug
can be formulated in admixture in one container, or can be
contained in separate containers for simultaneous or separate
administration. The kit can further comprise a device(s) for
administering the compounds and/or compositions, and written
instructions in a form prescribed by a governmental agency
regulating the manufacture, use or sale of pharmaceuticals or
biological products, which instructions can also reflect approval
by the agency of manufacture, use or sale for human
administration.
[0171] The foregoing description is considered as illustrative only
of the principles of the invention. Further, since numerous
modifications and changes will be readily apparent to those skilled
in the art, it is not desired to limit the invention to the exact
construction and process shown as described above. Accordingly, all
suitable modifications and equivalents may be resorted to falling
within the scope of the invention as defined by the claims that
follow.
[0172] The words "comprise," "comprising," "include," "including,"
and "includes" when used in this specification and in the following
claims are intended to specify the presence of stated features,
integers, components, or steps, but they do not preclude the
presence or addition of one or more other features, integers,
components, steps, or groups thereof.
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